Drug Companies Behaving Badly: What the Media Won't Tell You That You Need to Know

A recent article in the Newark Star-Ledger headlines that “drugmakers continue 'off-label marketing' despite large fines.”

In the last year, Pfizer agreed to pay $2.3 billion as settlement for allegations of illegal promotion of the arthritis med Bextra (pulled from the market) and other meds. Meanwhile, Eli Lilly agreed to pay $1.4 billion to settle criminal and civil charges for its off-label marketing of the antipsychotic med Zyprexa.

Around the same time, Johnson&Johnson’s Ortho-McNeil got slapped on the wrist for $6.4 million for its off-label promotion of the anti-seizure med Topamax for bipolar and other uses. The article mentions that the company paid physicians as much as $3,000 to accompany sales reps on doctor visits to “talk to you about things [the sales rep] can’t talk to you about.”

Earlier this year, Astra-Zeneca coughed up $18 million for marketing the antipsychotic Seroquel off-label to children and dementia patients.

Doing the math indicates that breaking the law is very good business practice. In 2004, Pfizer agreed to pay out $430 million for promoting the anti-seizure med Neurontin for bipolar and pain. Between 1999 and 2004, the drug raked in $10 billion in off-label sales.

Neurontin failed two clinical trials for treating bipolar. The drug itself may not have been harmful per se, but by promoting what was in effect a placebo with side effects the company was knowingly putting bipolar patients in harm’s way.

Thankfully, the Star-Ledger’s account stuck to the facts, which alone amounted to a ringing indictment on the drug industry. Too often, we see these stories in a far more emotional (and highly inaccurate) context, so let’s briefly re-examine some of the issues, which I have extensively reported on here and on mcmanweb and in my Newsletter and elsewhere:

The drug industry’s marketing practices are highly shameful. No question about it. This is where Enron meets BP meets Detroit. The industry, with the acquiescence of psychiatry, has been pulling one over on doctors, patients, and loved ones for years. I could write a book on this. Other people have.

The drug industry sets the agenda for psychiatry. Yes-no-maybe. Until a few years ago, this would have been a strong yes. But then, as patents for blockbuster meds began expiring and with no new meds (not just “me too” meds) coming on-stream, the drug companies lost interest in influencing psychiatry. “Ubiquity” is a term that no longer applies to drug companies, and thanks to new economic realities may never again.

At the same time, doctors and patients and loved ones, including the organizations that speak for them, have wised up. Fool me once ...

If a drug does not have FDA approval for a particular use, then it is dangerous for physicians to prescribe it for that use. Blatantly false. As Stephen Stahl of UCSD pointed out at an APA meeting: “The FDA regulates the sale of medicine, not the practice of medicine.”

FDA indications tend to be the end result of company marketing strategies, which figured into Eli Lilly and others initially seeking depression indications for their SSRIs, even though this class of drugs appears to work better for anxiety. Only later did these companies seek approval for the treatment of anxiety. So, was their “off-label” use in the interim bad medicine? Hardly.

As former head of the NIMH Frederick Goodwin pointed out at an APA meeting, new uses for meds are typically discovered and championed by clinicians in practice. The drug companies only come to the party later. If we were at the mercy of drug companies taking the initiative, bipolar patients would still be waiting for lithium, anti-seizure meds, and antipsychotics (there is not a single bipolar med developed by a drug company from scratch).

Despite this, the NY Times and other publications routinely (and ignorantly) equate off-label meds to rogue medicine.

“Powerful” drugs must be harmful drugs. Totally false. You will often read this in the context of doctors prescribing “powerful” antipsychotics” (off-label, of course) to kids for the “controversial” diagnosis of bipolar. Meds are supposed to be powerful. If you have any doubts about this, simply ask for a “weak” pain-killer next time your back gives out on you.

“Controversial” diagnoses (such as early-onset bipolar) have been manufactured by the drug companies to create new markets. Absurdly false. In this regard, the NY Times and other publications are difficult to distinguish from antipsychiatry diatribes. Academic food fights do exist, but hardly constitute evidence of fundamental splits of opinion. With regard to early onset bipolar, the diagnosis was promoted by - of all things - beleaguered parents educating disbelieving clinicians.

David Healy: But Is It Depression?

In a recent (and still ongoing) series on Robert Spitzer and the DSM, I touched on some of the history of the difficulties in separating out the diagnosis of depression from both bipolar and anxiety (part of what Freudians used to call neurosis). A different historical perspective is offered by David Healy MD (pictured here) of the University of Wales. I originally published this in an email newsletter back in Nov, 2003, and it has been featured on my website since Dec, 2003:

Consider these scenarios: A patient back in the seventies complains of "nerves" or anxiety and is sent out the door with a tranquilizer (benzodiazepine) such as Librium or Valium. A few years later, that same patient might be asking for Xanax for her panic attack. In the mid-nineties, we have the same patient with the same symptoms telling her doctor she has depression. Today, the same patient is likely once again to complain about anxiety.

Much of the credit for how we understand ourselves goes to the pharmaceutical companies, even if we don’t take meds, David Healy MD of the University of Wales said in a grand rounds lecture at UCLA on Oct 28, 2003 and webcast the same day. Upjohn (since taken over by Pfizer) pioneered the concept of marketing the illness rather than the drug, capitalizing on the DSM-III’s reclassification of anxiety into several disorders to push Xanax for panic disorder. In the mid-eighties, as the benzodiazepines became a focus of concern, the SSRIs in development were first seen as non-habit-forming alternatives to tranquilizers before they were targeted to treat depression. More recently, the SSRIs are returning to their original purpose, with the drug companies spending up to $100 million a year to promote these meds as "anxiolytics" (thereby distinguishing them from the bad associations of tranquilizers).

A thorn in the side of the psychiatric establishment, Dr Healy is the author of "Let Them Eat Prozac" and a dozen other books, has published articles on the suicidal side effects that some patients can experience on antidepressants, has appeared as an expert witness in legal actions against Prozac and Paxil, and recently sued the University of Toronto for rescinding an employment offer. According to Dr Healy, in order to create new markets for its products, the pharmaceutical industry ghost-writes much of the literature that appears in mainstream psychiatric journals, mobilizes expert opinion, designs its own drug trials, engages in extensive media campaigns, and underwrites (and even establishes) patients’ groups.

Dr Healy stressed to this writer that he is not hostile to the industry, simply stating that its influence needs to be recognized.

During the 1990s, Dr Healy went on to say, we converted cases that would have been treated by Valium and Librium into cases treated by Prozac, Paxil, and Zoloft. Back in the 1960s, an Eli Lilly print ad for a tranquilizer showed a young mom playing with her daughter. Another Lilly ad from the same period, by contrast, displayed the face of depression as an elderly woman. Back then, he reminded his audience, depression was regarded as a rare illness affecting mainly older people. In 1996, when the World Health Organization reported that depression was the second greatest source of disability on the planet, the reaction from psychiatry was not how did society become depressed so fast, but rather "we’re the second most important people in medicine after the cardiologists."

But this trend was far from universal, Dr Healy pointed out. During the nineties, the Japanese did not become depressed the way we did. Prozac is not on the market there [Note: this has since changed], and tranquilizer use remains vastly greater than antidepressant use. Most of the rest of the world, Dr Healy reminded his audience, follows the Japanese model.

Which raises the $64,000 question: Are we better off with antidepressants? The answer may elude us, if we follow Dr Healy’s reasoning. Randomized clinical trials, he says, were never meant to prove a treatment works. Rather, they are designed to show something doesn’t work, as in the case of a charlatan promoting snake oil. It is industry’s "greatest achievement," claims Dr Healy, to turn this around. Although he does prescribe antidepressants in his clinical practice, one senses it is with the confidence of one recommending a Tylenol for unexplained pain than an antibiotic to knock out a particular infection. Indeed, he concluded, if SSRIs worked for depression or anxiety the way antibiotics do for GPI (syphilis), we wouldn’t have the illness around anymore.

Don’t expect this guy to be the guest of honor at any industry-sponsored symposia.

More

In his UCLA grand rounds lecture, and in an internet article, Dr Healy gave several examples of how pharmaceutical companies influence medical and public opinion. One of these involved the company, Current Medical Directives (CMD), which ghost-writes and coordinates medical articles for its clients. As part of a legal action against Pfizer, Dr Healy obtained access to a document that listed the progress of 85 articles on Zoloft. Two articles in preparation related to Zoloft and PTSD, for which Pfizer was seeking a license. The authors were listed as "TBD," for "to be determined." The articles eventually appeared in JAMA and the Archives of General Psychiatry, with several academic psychiatrists credited as the authors. In a study published in the British Journal of Psychiatry, Dr Healy found that the 85 CMD articles were cited three times more often than non-CMD Zoloft articles. One hundred percent of the CMD articles reported favorable results for Zoloft vs 44 percent of the non-CMD articles.

Another example involved six academic articles on pediatric depression, with the authors hailing Paxil as "effective, safe, and well tolerated," despite clear evidence of suicidal thinking and behavior in some patients, greater than those on the placebo and comparison drugs. Since then, citing the same data the academic authors had access to, authorities in the UK have advised against prescribing Paxil to patients under age 18 while the FDA in the US has announced strengthened warnings on product labeling.

Postscript: In 2004, following two highly-publicized public hearings, the FDA announced that black box warnings advising of increased suicidal risk for non-adults would appear on antidepressant product labeling.

The Great Brain Robbery

In a recent blog post on Psychology Today, Nassir Ghaemi MD of Tufts University frankly discusses the "steroid problem of academia."

This concerns ghost authorship. What happens is common practice in journal publishing, especially in psychiatry. A drug company will design and write its own study, complete with its own spin favoring the drug in the study. Then the company invites respected academic researchers to front the study as authors. The study then appears in a medical or psychiatric journal. (For more detail how this works, check out my website article.)

What's in it for the "authors" is fame and academic distinction. In a university publish or perish environment, there is intense pressure on academics to rack up credits any way they can. The problem, says Dr Ghaemi, is that "some of our experts get their fame artificially, their achievements appearing greater than they really are."

In his blog, Dr Ghaemi reports how a department head actually encouraged him to engage in this type of fraud (he refused). Dr Ghaemi also reports how, fairly recently, a past president of the American Psychiatric Association and another luminary expressed complete surprise to him that this type of thing was going on. (This ignorance is astounding in light of the fact that eight or nine years ago, about a dozen journals worldwide ran simultaneous editorials highlighting the situation and promising corrective action in their own publications.)

Dr Ghaemi has devoted much of his professional life to researching the use of antidepressants in treating bipolar depression. His research has been influential in convincing psychiatrists to think twice before prescribing. His data shows that not only is the benefit problematic in a bipolar population, but there is risk of switching patients into mania and rapid cycling.

Not surprisingly, you will not find drug companies stampeding to fund studies to prove Dr Ghaemi right.

How serious is the problem? Early in 2008, in preparing for a grand rounds lecture I was to deliver to a psychiatric hospital in Princeton, I came across a 2006 study published in the American Journal of Psychiatry, which is put out by the American Psychiatric Association. The study concerned bipolar patients on Zyprexa, and was designed and written by Eli Lilly, which manufactures the drug.

The article listed Mauricio Tohen MD, DrPH as the lead author of the study. In all likelihood, Dr Tohen most likely did have a major hand designing and writing the study. A PubMed search of "Tohen M, olanzapine" reveals 92 published articles he authored between 1998 and 2008.

Dr Tohen is virtually unique in psychiatry in that he is affiliated with Harvard and Mass General Hospital AND is employed by Eli Lilly. In addition to Dr Tohen, the article listed eight other authors. Three of the names were instantly recognizable as prominent academic thought leaders.

According to the abstract of the study:

"Compared to placebo, olanzapine delays relapse into subsequent mood episodes in bipolar I disorder patients who responded to open-label acute treatment with olanzapine for a manic or mixed episode."

But the study data, not mentioned in the abstract, told a far different story. In fact, eighty percent of the patients in the study stopped taking their Zyprexa.

When I raised this to my audience of clinicians in my talk, I asked if anyone thought this was deceitful. All hands went up. I would go further, I said. I would say it's immoral.

Zyprexa is an antipsychotic with a high side effects profile, and it's not surprising that four in five bipolar patients choose not to take it, even if they are otherwise doing well on it. As Holly Swartz MD of the University of Pittsburgh told a symposium at the 2006 APA annual meeting: "If a patient doesn’t stay on it, it doesn’t do any good, even if it works.”

No doubt, I ranted and raved far too much in my talk, but as a patient I represent the greatest stakeholders in this debate. Am I going to end up in crisis - or worse - as a result of a well-meaning doctor sending me out the door with the wrong prescription based on deliberate misinformation?

Does anyone see a blatant violation of the "do no harm" principle at work?

I have no objection to productive partnerships between industry and academia. Indeed, drug companies would be incredibility stupid not to tap into this invaluable brain trust. Likewise, academics deserve to profit handsomely from any research that improves our chances of leading productive and rewarding lives.

What I object to is drug companies debasing psychiatry by employing its best and brightest as errand boys. Meanwhile, far too many highly-dedicated researchers are forced to leave the field due to lack of funding. We are left struggling in the dark. Our doctors get treated to infomercials.