Of Seroquel, Sex, and Secret Documents

Seroquel (generic name, quetiapine) is an atypical antipsychotic that made a tidy $4.4 billion for AstraZeneca last year. Seroquel’s golden goose status is based on a string of FDA approvals for schizophrenia, mania in bipolar disorder, and more recently, depression in bipolar disorder. In addition, it is commonly used off-label for insomnia, and the company is applying for FDA approval for the treatment of generalized anxiety disorder.

The drug’s approval for bipolar depression was particularly valuable, because it opened the door to off-label use in garden variety, unipolar depression—a much bigger market than bipolar depression. The problem is that the “BOLDER” studies, which formed the basis for FDA approval, had a glaring weakness. The patients who were enrolled were very different from the patients we see in clinical practice. The BOLDER studies excluded patients with:

--Current depression lasing longer than 12 months
--Substance use within 12 months
--Any other recently treated psychiatric disorders
--Suicidal ideation

In addition, any patients who had tried and not responded to two previous trials of antidepressants were not eligible for the study. This restriction is especially problematic, because by the time most real patients get the diagnosis of bipolar depression, they have already been on many rounds of antidepressants.

Thus, Seroquel is approved for a very special and unusual kind of depressed bipolar patient—someone who is who is unlikely to be seen by practicing psychiatrists. The patients I see are sicker and much more complex; prescribing Seroquel for them may or may not make them better, but is all but certain to cause significant weight gain, rendering them more vulnerable to heart disease and diabetes.

Which is all a very long-winded introduction to the latest scandal-in-the-making from AstraZeneca. As covered in BusinessWeek, and the Furious Seasons blog, AstraZeneca is being sued by thousands of patients who allege that the company hid information about Seroquel’s risk of weight gain and diabetes. 6,000 claims have been consolidated into a single case before a federal court in Orlando Florida.

Reams of documents have been shipped in by AstraZeneca related to the case, but none have been disclosed yet, because no actual trial has commenced. It is possible that in order to avoid disclosure of embarrassing documents, the company will settle the case and prevent a trial. But the news agency Bloomberg has filed a motion to force these documents to be unsealed, citing “the public's right of access to judicial documents."

Presumably, these documents will be just as damaging as the leaked Zyprexa documents which showed that Lilly’s “Viva Zyprexa” campaign deliberately encouraged primary care doctors to prescribe Zyprexa for unapproved uses.

Maybe more damaging, actually, because at least the Lilly documents did not involve a senior company scientist having sex with a company funded researcher and a ghostwriter. That’s right, folks—according to one publically available court document, the company’s lead research director, Wayne Macfadden, was getting awfully busy with women who did Seroquel research and wrote up the BOLDER results.

The document alleges that Macfadden's relationships with the women were "relevant and highly probative evidence of one high level AstraZeneca employee's determination to exploit his sexual relationships with these women in order to elevate Seroquel's status in the prescribing medical community through supposedly 'independent' publications of Seroquel safety and efficacy data….Moreover, the mere existence of these relationships calls into question the integrity of the scientific work product of those involved."

We don’t know if all these allegations are true, although Macfadden has already admitted to the dalliances.

At this point, AstraZeneca needs to do the right thing, which is to unseal the secret documents. Only then will the company be able to clear its name.

Marketing Surveys and the Politics of CME

Recently, this survey of physician opinions about industry funding of CME has been circulating through various blogs and listservs. The lead paragraph will give you a flavor of who stands to benefit from the results:

NEW YORK, NY – January 27, 2009 – A study by healthcare market research firm Manhattan Research found that only 9% of U.S. physicians oppose commercial support for continuing medical education (CME) funding. The results of this study are relevant to the ongoing discussion in the medical community about the role of commercial funding of CME.

The results have been accepted at face value by various stakeholders in the commercial CME industry, but I was skeptical, because the survey was neither published nor peer reviewed, and the press release did not describe the survey’s methodology.

The surveys results were at odds with the most methodology sound CME survey in the literature, which was published in the American Journal Medicine. This study, conducted at the Mayo Clinic, clearly described their sampling procedures and spelled out all relevant demographics. Two different groups of physicians were sampled, those who were attending an industry-supported CME course, and those were attending a non-supported course. Most doctors who attended the non-supported course believed that industry-supported CME is biased (52.7% answered “yes,” 37.6% answered “no”). On the other hand, doctors attending the industry supported symposia tended to believe that they are not biased (24.3% "yes," 63.7% "no").

The bottom line of this survey is that opinions about commercial support of CME depend entirely upon which physicians you sample. If you choose to sample doctors who are in the midst of a free conference with the nicest meals, the flashiest slides and the biggest names that industry money will buy, they will defend the wisdom of their choice. But if you sample physicians who choose to pay for their own medical education, you will find that doctors overwhelmingly reject industry funding of CME.

Which physcians did Manhattan Research sample? I asked Mark Bard, president of Manhattan Research, who wrote me that: “The physician sample was a nationally (US) representative mix of primary care and specialists (total of 904 physician respondents) and reflective of national norms for age, gender, region, and practice setting.
Although the survey was completed online, they were recruited by phone, fax, and email (to the panel).”

I’ve asked him the crucial question of how this particular sample was identified, but I have yet to receive an answer.

On its website, Manhattan Research describes itself as “a pharmaceutical and healthcare market research and services firm that helps healthcare and life sciences organizations adapt, prosper and explore opportunities in the networked economy.” Their client list includes 11 drug companies (including Pfizer, GlaxoSmithKline, Johnson and Johnson, Abbott, and Wyeth) and two giants in the medical education industry (WebMD, owner of Medscape, and Elsevier).

I find it sad, though quite revealing, that the CME industry has found it necessary to latch onto this non-peer reviewed survey in order to further its political aims.

Ski Week

Blog Carlat has taken advantage of school vacation week in Massachusetts to corral the posse and head up to the New Hampshire mountains. We'll be back on Monday!

Notes from the Battleground

British Medical Journal focuses on industry/physician relations.

There are several editorials in the current issue of the British Medical Journal on the proper distance (or lack thereof) between doctors and the pharmaceutical industry. My favorite among them is Marcia Angell’s commentary, which can be found (for free) here. It begins with the following very clear message, and continues in a similarly powerful way:

"I believe there should be no relationship between the drug industry and either prescribers or patients. Drug companies are investor owned businesses with a responsibility to maximise profits for their shareholders. That is quite different from the mission of the medical profession, which is to provide the best care possible for patients. I start with this simple fact, because it is so often obscured by the industry’s public relations. Drug companies are not confused on this score. Their major output now consists of "me-too" drugs for mild or ill defined conditions in essentially healthy people. This is because that market is big and more easily expanded than the market for innovative drugs for serious diseases."

Doctor's group is allergic to the rules.

The American Academy of Allergy, Asthma and Immunology has decided that it doesn’t like the official rules governing continuing medical education. According to the Boston Globe, the medical society has decided to cancel its scheduled 2015 meeting in Boston because of restrictions on drug marketing passed by the Massachusetts legislature.

Specifically, these physicians don’t want to have to adhere to ACCME’s national standards for commercial support:

“The state's rules say that continuing medical education courses, which doctors must take to keep their licenses, must comply with guidelines issued by the Accreditation Council for Continuing Medical Education. Kay Whalen, executive director of the allergy academy, and David Bodine, president of the gene therapy society, said this requirement is a major problem.”

I have some bad news for Ms. Whalen: ACCME guidelines apply in every single city, town and hamlet in the U.S. You can run, but you can’t hide.

"When the sun goes down in Las Vegas, steer clear of doctors."

So goes the catchy subtitle of this great article by Barry Meier in the New York Times. It concerns the ethically troubled orthopedic device industry, which specializes in paying prominent orthopedists millions of dollars per year to “consult” and “educate” regarding their devices.

The American Academy of Orthopedic Surgeons will hold its annual meeting at the Venetian/Sands expo in Las Vegas later this month, and Smith and Nephew, the leading maker of artificial hips and knees, has instructed its reps not to talk to surgeons after 5 pm, presumably to lessen the possibility of shady consulting deals. But, according to the article, “It remains to be seen whether such seeming magnets as doctors and sales executives can resist each other.”

So true.

Great Britain May End Industry Support of CME

Great Britain’s Royal College of Physicians , which is in charge of accrediting continuing medical education, has just issued a report recommending, among other things, that industry funding of CME programs be gradually eliminated.

The report, a summary of which is posted here, is entitled “Innovating for health: Patients, physicians, the pharmaceutical industry and the NHS.”

This report was developed by a work group chaired by Richard Horton (Editor-in-Chief of The Lancet), with representatives from the pharmaceutical industry (including Pfizer and GlaxoSmithKline), academia, and the National Health Service.

The report’s specific recommendation regarding CME was:

“Decoupling the pharmaceutical industry from continuing professional development [this is Great Britain’s term for continuing medical education]. The industry presently pays for about half of all postgraduate medical education. In order to address widespread suspicions that drug promotion is carried out through continuing professional development, the working party recommends weaning postgraduate training off individual pharmaceutical company sponsorship over a time bound period while alternative sources of sustainable funding are organised through for example the royal colleges and the Department of Health.”

Other recommendation included:

· The creation of a program that could provide independent sources of evidence about the effectiveness of different prescription drugs for consumers.

· The creation and adoption of consistent ethical guidelines regarding relationships between doctors and pharmaceutical companies.

· Better collaboration among medical researchers from government, academia, and industry.

I hope that our own ACCME will study this document carefully, and will adopt the same recommendations.

(Hat tip to Kate Peterson and the Prescription Project for alerting me to this item).

FDA Candidates, Through The Carlat Lens

According to Reuters, President Obama will be naming his choice for FDA Commissioner within “days.” Most sources say that he has narrowed his choices down to the following four candidates: Joshua Sharfstein, head of Baltimore's health department; Robert Califf, cardiologist at Duke University; Cleveland Clinic cardiologist Steve Nissen; and Susan Wood, former head of the FDA's Office of Women's Health. However, the rumor mill seemingly churns hourly--now, according to Drug Wonks, former New York City Health Commissioner Margaret Hamburg is also in the running (Hamburg's name surfaced too late for me to give her a mini-review).

I’m not sure who I would pick. I personally know Dr. Steve Nissen and think he would be an fantastic choice, because he amply understands the challenges and imperfections of the FDA and has clear plans for fixing the agency. And, of course, it doesn’t hurt that he has never been afraid to call out drug companies for hiding inconvenient data about drug side effects. Dr. Nissen, if you’ll recall, was the one who broke the Avandia story . But he is hardly anti-pharmaceuticals. As chair of cardiovascular medicine of the Cleveland Clinic, he has conducted industry-funded research, and he has focused on using intravascular ultrasound (IVUS) imaging for treating coronary atherosclerosis. His disclosures are listed here, but note that he receives no personal income from these relationships, insisting that companies donate all honoraria to charity.

Susan Wood is another great choice. A heroine when it comes to women’s rights, Wood was the FDA’s Director of the Office of Women's Health until 2005, when she resigned on principle over the delay in approving “Plan B,” an emergency over–the–counter contraception (not to be confused with the “abortion pill,” RU-486). She is currently a professor in the School of Public Health at GW University. You can read up on her here and here. As far as I know, she has no financial relationships with any pharmaceutical company, and she is the only candidate who is not an M.D., for better or for worse.

Josh Sharfstein, who is currently head of the Baltimore Health Department, has an interesting psychiatric connection in that his father, Steve Sharfstein, is the former president of the American Psychiatric Association. Steve Sharfstein made a splash by publishing this column in which he urged clearer boundaries between physicians and industry enticements. Josh Sharfstein has an equally strong sense of ethics, and has in the past called Pfizer onto the carpet for improper promotion (he once alerted the New England Journal of Medicine that Pfizer was inviting docs to a “rack ‘em up and toss ‘em down” event including billiards and lots of alcohol). He has also worked on the staff of Representative Henry Waxman, who is now chair of the powerful House Energy and Commerce Committee. Sources tell me that he has no financial relationships with the pharmaceutical industry.

The only truly bizarre entry on Obama’s short list is Dr. Robert Califf, vice chancellor for clinical research and professor in the cardiology department at Duke. I have no problem with his experience and extraordinary academic achievements. And I hesitate to criticize a fellow grad of UCSF Medical School. But c’mon folks, look at these industry disclosures. He took money—lots of money--from 18 different pharmaceutical or device firms. Most of this was not for research, but for consulting and speaking, including CME. If Dr. Califf believes that it is ethical for physicians to help drug companies market their products, that’s his own business. But to elevate him to a position in which he is the country’s chief watchdog over unsafe medications and foods seems a dangerous move. With money from 18 drug companies padding his bank account, he will presumably spend most of his FDA career recusing himself from crucial decisions. Not a good idea.

So, Mr. President, in my opinion you can’t go wrong with Nissen, Wood, or Sharfstein—but please keep Dr. Califf out of the running.