Sunday, December 28, 2008

Emory lets Nemeroff off the hook

Three days before Christmas, Emory University gave its long-time chief of psychiatry a nice holiday gift: in return for his stepping down as psychiatry head, university officials are allowing Charles Nemeroff to stay at the university as a full professor despite his failure to disclose hundreds of thousands of dollars in personal payments from GlaxoSmith Kline, the maker of Paxil. According to Pharmalot, Emory justified its milk-toast action by saying that a review of Nemeroff's speeches supported his contention that his lectures were not product-specific but rather limited to general medical topics such as depression and bipolar disorder.

Somehow I seriously doubt that. Why? Because over the years Nemeroff has most definitely given product-specific lectures on behalf of drug companies. As I note in Side Effects, Nemeroff spoke on behalf of Eli Lilly, the maker of Prozac, during the pivotal 1991 FDA hearing on concerns that Prozac increased the risk of sucidal thoughts and behaviors among patients taking the SSRI antidepressant. (At the time, Nemeroff had lucrative consulting arrangements with Eli Lilly and also owned stock in the Indianapolis-based drug company). As part of his presentation to the FDA, Nemeroff specifically talked about the available research on Prozac and other SSRI antidepressants (including Paxil) and went so far as to dismiss case reports then emerging about the suicidal risks of these drugs. According to people who attended that hearing, Nemeroff's "elegant" and very product-specific lecture that day helped convince the FDA advisory board to dismiss concerns about these drugs' side effects. As a result, it took the federal agency another 13 years to put black box warnings about the suicidal risks on Prozac, Paxil and other antidepressants.

In concluding its investigation (back story), Emory said it found no evidence that Nemeroff's consulting activities biased scientific research. It seems obvious that university officials weren't looking very hard.

For now, at least, the university will be keeping Nemeroff on a tight leash -- he has to get prior approval for any and all outside speaking and consulting engagements and is not allowed to be involved in any NIH-funded research for at least two years. By then, hopefully, Congress will have passed the Physician Payment Sunshine Act, so when Nemeroff does start doing research again on the taxpayer's dollar, his take from the drug companies will be a matter of public record.

Thursday, December 18, 2008

Ghostwriting: an old and venerable practice

I'm delighted to see that The New York Times has discovered the problem of ghostwriting -- wherein drug companies pay shills to write medical journal articles and then go hunting for respected doctors to put their names on already prepared articles. And I can only applaud the work being done by Senator Charles Grassley's team that led to the Times' article Friday on the ghostwriting behind several journal articles promoting Wyeth's hormone replacement drug Prempro (even after a federal study found the drug raised the risk of breast cancer).

But let's not kid ourselves: ghostwriting by the pharmaceutical industry is neither new nor uncommon. The British psychiatrist and historian David Healy was among the first to write about this widespread practice, when he published a 2003 article in The British Journal of Psychiatry about Pfizer's ambitious ghost-writing efforts to promote its antidepressant, Zoloft, in numerous medical journals. Healy showed that, similar to what Wyeth did with Prempro, Pfizer ginned up a publication plan that indicated all of the studies it had going on Zoloft (sertraline), who the authors were, and what the status of publication for each article was. As Pfizer's plan indicated, most of these articles had originated with ghostwriters (in this case a company called Current Medical Directions) and a number of the planned articles listed the authors as "To Be Determined."

GlaxoSmithKline did the same thing in promoting its blockbuster antidepressant Paxil, as a number of books, my own included, have revealed. According to documents unsealed in a lawsuit, Glaxo hired a ghostwriter by the name of Sally Laden (from Scientific Therapeutics Inc.) to write the first draft of a study comparing Paxil to placebo and an older antidepressant in treating depression among adolescents. The study purported to show that Paxil was more effective than placebo and the older tricyclic, even though the actual data showed that the opposite was true; see back story. As the legal documents show, the principal researchers of study 329, as it became known, made only minimal changes to the ghost-written draft, and it was Laden who, with the help of Glaxo officials, shopped it to several journals, before finally getting the article published in The Journal of the American Academy of Child and Adolescent Psychiatry in 2001. Glaxo then used the JAACAP article to heavily market Paxil for pediatric use to doctors in the U.S. (even though such off-label marketing is supposed to be illegal).

Because of the publicity over such flagrant abuses, one former journal editor says that most leading journals now require the authors of submitted manuscripts to attest to the fact that they have written the paper's first draft or tell the journal who did write it. So while that may cut down to some extent on ghost writing, it doesn't mean the practice will disappear. After all, the journals still have to take the researchers' word for it. And that word, as has been demonstrated over and over again in the case of doctors on the take from drug companies, doesn't necessarily mean all that much.

Thursday, December 11, 2008

Massachusetts officials allow huge loophole in new drug payment disclosure regulations

Kudos to The Boston Globe for revealing a big loophole in Massachusetts' new disclosure rules for health professionals: doctors who receive lucrative consulting and research funding from drug companies do not need to disclose these payments under the proposed regulations.

The new rules would require Massachusetts physicians from accepting free meals, gifts and vacation junkets from drug companies and mandate that they report any money they receive to promote drug company products. However, according to a memo from the Health and Human Services' deputy general counsel, the proposed regulations do not cover "bona fide services" for drug and medical device manufacturers such as consulting services, research, participation on advisory boards, company-sponsored presentations and education.

In other words, the disclosure requirements won't cover the kind of back-room payments to doctors that create the conflicts of interest that health advocates worry about most. As Tufts University professor Jerome Kassirer, author of On the Take: How Medicine's Complicity with Big Business can endanger your Health told The Boston Herald yesterday, "We shouldn't be hiding any kind of personal relationships between pharmaceutical companies and physicians, because of the possibility that any kind of money that goes to physicians could produce some sort of bias."

Not could, does. Research shows that doctors who receive personal payments from drug companies are much more likely to report and promote positive findings about the company's products than doctors who don't have these conflicts.

In a statement, Massachusetts Public Health Commissioner John Auerbach said the state's public health council allowed the loophole to keep clinical trials in the state. In other words, it caved into pressure from the drug and medical device companies.

It looks like we're going to have to wait for passage of the national Physician Payment Sunshine Act to get any kind of meaningful reform. That law, introduced by Sen. Chuck Grassely last year, would require companies to disclose any payment they made to health professionals in excess of $500 per year (back story). Unless, of course, Massachusetts citizens decide they've had enough and make their voices heard at the two public hearings being held on the new regs in January; see press release.

Wouldn't that be a hoot?

Wednesday, December 3, 2008

New study confirms: bias in the publication of drug trials is widespread

In its landmark lawsuit against GlaxoSmithKline, the New York State Attorney General accused the pharmaceutical giant of consumer fraud for not publishing negative findings about its antidepressant, Paxil, in essence, for not giving doctors and consumers the full story about its blockbuster drug.

Now comes a new study showing that the practice of selectively publishing only positive results and suppressing negative findings is an industry-wide habit. In a study published last week in PLoS Medicine, researchers at the University of California San Francisco discovered that only three-quarters of the randomized drug trials submitted for New Drug Applications (NDAs) between 2001 and 2002 were eventually published. Even more worrisome, trials with favorable outcomes were nearly five times more likely to be published than those with negative outcomes.

Furthermore, the researchers found evidence that primary outcomes were changed between the time the results were submitted to the FDA as NDAs and the time the studies were published. And when that happened, the results were invariably altered to favor the test drug, the researchers found.

These findings demonstrate that "the information that is readily available in the scientific literature to health care professionals is incomplete and potentially biased," the UCSF researchers conclude.

In an accompanying editorial, a scientist for the Mayo Clinic who previously worked with the World Health Organization's International Clinical Trials Registry Platform, agreed that the "trial literature is biased" and declared that the "the time has come to tackle the challenge of making key trial documents public."

Fortunately, drug companies are now required by law to post the results of all their clinical trials, negative as well as positive, on a publicly available website. And the fact that the leading medical journals now require pretrial registration -- i.e. researchers must post their trial protocols on a public website -- should help cut down on the tendency to change primary outcome measures to favor drug results.

However, drug company-sponsored researchers still don't have to publish the results of all randomized drug trials in medical journals. And since that is where doctors and consumers get most of their information, the full story about the safety and effectiveness of new drugs remains untold.

Tuesday, November 25, 2008

Biederman's conflicts: a crime against troubled children and the State?

If I were the parent of a child diagnosed with bipolar disorder by doctors at Massachusetts General Hospital and prescribed anti-psychotic drugs with serious side effects, how would I feel upon learning that the head honcho of MGH's child psychiatry department not only was on the take from the makers of these powerful drugs but pushed for the establishment of a drug company-funded center at MGH whose stated "rationale" was "to generate and disseminate data supporting use" of these drugs in children?

Betrayed is how I would feel, horribly betrayed.

Moving beyond the issue of betrayal, the actions of Joseph Biederman, as revealed today in The New York Times and The Boston Globe, raise the specter of criminality. By pushing Johnson & Johnson, the maker of Risperdal, to fund a center at MGH whose stated goal was to support the use of Risperdal and "move forward the commercial goals of J&J," the question emerges: did Biederman help Johnson & Johnson illegally market the off-label use of its anti-psychotic drug in children and adolescents?

While it is legal for doctors to prescribe drugs for uses not approved by the FDA, it is illegal for companies to actively market those off-label drugs. As a number of recent books, Side Effects included, show, drug makers routinely got around that restriction by recruiting and paying key opinion leaders to promote the off-label use of their products at medical conferences, company-sponsored meetings and in medical journals. By taking millions of dollars, both personally and to fund his MGH center, Biederman seems to have raised the art of off-label promotion to an entirely new level.

As The New York Times reports, "Biederman's work helped to fuel a 40-fold increase from 1994 to 2003 in the diagnosis of pediatric bipolar disorder and a rapid rise in the use of powerful, risky and expensive anti-psychotic medicines in children... Biederman had a vast influence on the field largely because of his position at one of the most prestigous medical institutions in the world."

Earlier this summer, Congressional investigators led by Senator Charles E. Grassley accused Biederman of failing to disclose at least $1.4 million in personal payments from companies that make anti-psychotic drugs, such as Risperdal, Zyprexa, Abilify and Seroquel (back story). Now comes the news, as revealed in documents unsealed in a lawsuit, that Biederman repeatedly pushed Johnson & Johnson to fund a center at MGH whose stated purpose was to spread the word about Risperdal in treating bipolar disorder in children. Emails unsealed from the multi-state lawsuit also reveal that Biederman was asked to author a study of Risperdal ghost-written by Johnson & Johnson that purported to show the drug was more effective than a placebo in treating children.

In other words, we give you money to fund your center and line your pockets and you spread the word about our wonderful drugs, medical objectivity be damned.

Here is another example of how the tort system that the drug company lawyers are pushing to abolish helps consumers. The reason these documents came to light is because thousands of parents sued J&J, AstraZeneca (the maker Seroquel) and Eli Lilly (the maker of Zypreca), claiming that the companies minimized the risks of the anti-psychotic drugs given to their children. Attorneys representing these families demanded reams of documents from the companies, and while nearly all of these documents remain under seal, a select few that mentioned Biederman became public as part of an effort to compel the MGH psychiatrist to testify under oath as a witness in the legal proceedings. (The plaintiffs won and Biederman is expected to be deposed sometime in January, according to The Boston Globe).

So the question becomes: how long will Mass. General and Harvard Medical School allow such unethical and possibly criminal behavior to tarnish their reputations? Hopefully not long.

Wednesday, November 19, 2008

Drug Industry Mantra: If you can't buy them, bully them?

I found a disturbing common thread emerge this week from news coverage of the medical-pharmaceutical industry, a thread that can be summed in these words: If you can't buy them, bully them.

First off, we have reports in The New York Times and Pharmalot that an FDA advisory panel concluded that powerful anti-psychotic drugs are being prescribed much too readily to children; the panel called on the FDA to do more to discourage the use of these drugs in children diagnosed with bipolar disorder. As Gardiner Harris of The New York Times notes, "the leading advocate for the bipolar diagnosis is Dr. Joseph Biederman, a child psychiatrist at Harvard University whose work is under a cloud after a Congressional investigation revealed he had failed to report at least $1.4 million in outside income from the makers of antipsychotic medicines."

Biederman, as this and many other blogs have noted, is just one of many doctors who failed to fully disclose the extent of their earnings from the makers of drugs whom they were, at the same time, studying and touting to colleagues. As I reveal in Side Effects, this is simply the way the drug industry does business: they recruit prominent doctors, called key opinion leaders (KOLs), and pay them lots of money to promote new drugs to other doctors. Such blatant conflicts of interest are only now being widely publicized due to the diligence of Sen. Chuck Grassley's Finance Committee. That's the carrot side of the equation.

Now, we find that the drug industry also used the stick to intimidate doctors who spoke up about the worrisome side effects of some drugs. The Wall Street Journal and Pharmalot today reported that GlaxoSmithKline attempted to intimidate a physician at a Maryland hospital to stop her from voicing concerns about its antidiabetes drug, Avandia. In 2000, Dr. Mary Money and several colleagues at Washington County Hospital in Hagerstown raised concerns with both the company and the FDA that Avandia increased the risk of heart failure. GlaxoSmithKline dismissed their concerns and then wrote a letter to the hospital's chief of staff demanding he take immediate steps to "stop the dissemination of unsubstantiated information by your medical staff."

We also learn that another physician from Duke University testified before Congress that he too had been attacked as a liar and threatened with a lawsuit by the drug company when he raised concerns about Avandia. It was not until 2007, after The New England Journal of Medicine published a meta-analysis showing an increased risk of heart failure among patients taking Avandia, that the FDA put black box warnings on the drug. (It's worth noting that researchers would never have been able to do this meta-analysis if not for the New York State Attorney General's lawsuit against GlaxoSmithKline for deceiving physicians and consumers about another of its drugs, the antidepressant Paxil; as part of settling that lawsuit, Glaxo agreed to post the findings of all its clinical trials, including those about Avandia).

So what's the common theme in all of this? If the drug industry can't buy doctors to promote their new drugs, then they will do what they can to bully them into silence. For shame.

Thursday, November 6, 2008

New Zoloft study: an eerie case of deja vu

Between teaching journalism and working on my master's thesis, I have only now found the time to scrutinize the much-heralded Zoloft study published last Friday in the online version of The New England Journal of Medicine. And I have a few bones to pick with it, some of which have already been picked by commentators on Pharmalot.

The study found that a combined regimen of Zoloft and cognitive behavior therapy was more effective than either the drug or therapy alone in treating anxiety in children (age 7 to 17). It also concluded that Zoloft and CBT by themselves were more effective than placebo. News accounts of the study trumpeted the fact that none of the children in this trial committed suicide and that there was no significant increase in suicidal thoughts among those taking Zoloft. By highlighting these findings, the study's researchers no doubt intended to add weight to the argument that the FDA acted too hastily back in 2004 in putting black box warnings on Zoloft and other antidepressants.

Not so fast please. If you look closely at the data in this study, there are indications that a number of children taking Zoloft did have adverse reactions to the drug and experienced "a worsening" of psychiatric behaviors, in one case so severe that the child required hospitalization. Indeed of the three children in thte study who had serious adverse effects, two of them were in the Zoloft only arm of the study and one in the combination arm. Yet the study researchers dismiss the case requiring psychiatric hospitalization as being "unrelated to the study treatment."

This language of blithe dismissal is eerily reminscient of another antidepressant trial: Paxil study 329, which is currently under investigation by the U.S. Department of Justice back story. In study 329, researchers not only dismissed some adverse effects as being unrelated to Paxil, but they also concluded that Paxil was more effective than placebo, when in fact the data showed it was not. (As I reveal in my book, Side Effects, Brown University researchers also misrepresented data in the trial, coding teenagers who were suicidal as being "noncompliant."

Indeed, as Doug Bremner, professor of psychiatry at Emory University, points out on Pharmalot, the results of this study are not that different from the non-statistically significant results in the Paxil study. In that study, Paxil was found to be no more effective than placebo on the two primary outcome measures. In the more recent Zoloft study, Bremner notes that when you look at the actual data on one of the primary outcomes, the Pediatric Anxiety scale, the difference in improvement between the patients in the Zoloft only arm and the patients in the placebo group are also not statistically significant. Bremner dissects problems with the Zoloft study in greater depth on his blog.

There's more. The Zoloft study also minimizes the fact that of the 14 patients who withdrew from either treatment or the study due to adverse side effects, most of them were in the Zoloft only group. While its authors make much of the finding that there were no patients with suicidal thoughts in the Zoloft only group, they gloss over the fact that there were five patients who expressed suicidal ideation in the combined Zoloft/CBT group.

The researchers also ignore the finding that overall, there were many fewer side effects among the children in the cognitive behavior therapy group alone; patients in the latter group reported fewer cases of insomnia, fatigue, sedation, restlessness and fidgeting than those in the Zoloft study. That makes a lot of sense given the research showing that there is an increased risk of akathasia (agitation and restlessness) among patients who take SSRI antidepressants like Zoloft, Prozac and Paxil.

Finally, the Zoloft trial shares another disturbing similarity with Paxil study 329: in the fine print at the end of the NEJM report, its researchers disclose a myriad of financial ties to the pharmaceutical industry, including extensive consulting and speaking fees from companies that make SSRI antidepressants. So as several of the Pharmalot commentators ask, why should we trust the conclusions of this study? Why indeed.

Tuesday, October 28, 2008

Exposing the drug industry's bogus $800 million cost estimate... and other sordid tales

In 2003. researchers at Tufts University published a study showing that it cost drug companies approximately $800 million to develop a new drug and get it approved by the FDA. In the intervening years, the drug industry has used that mind-boggling cost estimate to justify not only the high cost of new prescription drugs but also the need for expedited drug approvals and long patent protection once their drugs were approved.

Well, guess what? As it turns out, the study by researchers for the Tufts Center for the Study of Drug Development was deeply flawed and wildly inflated the actual cost of developing a new drug from start to finish. The study’s flaws and the undisclosed conflicts on the part of its authors were dissected both in a book by Merrill Goozner, the author of gooznews and in a paper that two bioethicists tried to get published in the Journal of Health Economics, which ran the original $800 million estimate.

In a tale that rivals anything out of Machiavelli, the editors of this supposedly respectable journal insisted on massive revisions and cuts in the bioethicists’ submission and only agreed to publish a milder version of their critique after the two threatened to sue the journal for violating academic freedoms. The JHE editors were particularly adamant about cutting from the critique the fact that authors of the $800 million estimate had failed to disclose in their study that they and the Tufts Center for the Study of Drug Development are heavily dependent on drug industry funding (although it didn't fund the cost estimate study).

The two bioethicists, Donald Light, a professor at the University of Medicine and Dentistry in New Jersey, and Rebecca Warburton, a health economist at the University of London, chronicle their convoluted efforts to publish their critique -- in an entertaining piece in the current issue of the Harvard Health Policy Review. They hold their experience up as an example of the need for higher ethical standards on the part of many conflict-ridden healthcare journals.

But wait – the story doesn’t end there. According to Gooznews, the editor of the student-run Harvard Health Policy Review yanked the entire issue of HHPR off the web last week after getting a steamed email from Richard Frank, one of the editors of JHE who also happens to be the Harvard review's faculty advisor and a big-time health economics professor at Harvard Medical School. In his email, Frank said he no longer wanted to be affiliated with the review. As the student editors now admit, “we panicked.”

The current issue is now back online along with an abject apology from the student editors for not having fact-checked the Light/Warburton critique to ensure the veracity of their claims. Apparently, what most incensed Richard Frank was that the HHPR didn’t contact the JHE editors for rebuttal before running the critique.

Funny how some powerful journal editors don't enjoy being on the receiving end of their own medicine.

Wednesday, October 22, 2008

New study of suicide rates reveals: the emperor has no clothes

A bewildered tone seemed to permeate the news reports this week that suicide rates among middle-aged Americans rose sharply from 1999 to 2005. Even the authors of the new analysis in the American Journal of Preventive Medicine said they had no idea why the suicide rate climbed 19 percent among white women ages 40 to 64 and 16 percent among white men of the same age during those six years. As Susan Baker, an epidemiologist at Johns Hopkins School of Public Health said in The Boston Globe yesterday, “I have no idea what’s going on with this age group.”

Could it be that some of the confusion stems from the fact that this new data puts the lie to the drug industry’s long-held contention that antidepressants known as selective serotonin reuptake inhibitors (SSRIs) lead to fewer suicides? After all, during roughly the same time period, antidepressant prescriptions in the United States rose 10 percent, according to a survey by the federal Agency for Healthcare Research and Quality. In a statistical brief published in June 2008, the AHRQ noted that the number of antidepressants purchased in the U.S. rose from 154 million in 2002 to 170 million in 2005. So if antidepressant prescriptions and suicide rates among middle-aged adults were both rising during the first five years of the 21st century, drugs like Prozac, Paxil, Zoloft and Celexa are obviously not stemming the tide.

So what does explain the sharp rise in suicide rates among folks that (unlike teenagers and the elderly) are not known for having a high risk of self-in jury? One explanation could be the economy. Research has shown that suicide rates tend to rise during periods of economic hard times and decline during good times. And as we all know, with the burst of the dot com bubble in 2000, the American economy slid into a recession for the next three or four years.

That correlation has prompted some observers to voice concerns about what might happen with the current financial meltdown. Newsday quoted Alan Berman, executive director of the American Association of Suicidology (AAS), saying he feared the struggling economy could accelerate the trend. “We know that unemployment affects suicide rates and that when people feel a severe economic strain, suicide rates tend to increase among people experiencing this trend,” Berman said.

I find it interesting that neither Berman nor any of the experts quoted in the news raised the issue of antidepressants and what role they may (or may not) play in the rising suicide rates. No one, it seems, least of all organizations like the AAS, which derives a lot of its funding from drug companies, are eager to call attention to the likelihood that the Emperor has no clothes.

Wednesday, October 15, 2008

Let the Sun Shine in on Research Conflicts

The Senate Finance Committee’s probe of physicians with extensive financial conflicts is gathering steam: first, Stanford University removed its psychiatry chief Alan Schatzberg as principal investigator of a federally funded study after Congressional investigators discovered that he owned $6 million of stock in a company whose drug he was studying and touting in medical journals (back story). Then last week, Charles Nemeroff, the dean of American psychiatry, was asked to step down as chief of psychiatry at Emory University after the same investigators found that he failed to fully disclose to Emory much of the thousands of dollars in consulting and speaking fees he was earning each year from companies whose drugs he too was promoting (back story). Most recently, the National Institutes of Health (NIH) has announced that it is freezing a $9.3 million, five-year grant to an Emory University center for research on treatments for depression, according to The Atlanta Journal-Constitution .

But while the NIH has finally been scolded into enforcing its own decades-old conflict of interest policies, legislation that would mandate the public reporting of such financial conflicts remains moribund. The Physician Payment Sunshine Act, introduced last year by Sen. Charles Grassley (R-IA), a ranking member of the Senate Finance Committee, would mandate the public reporting of payments (over $500 in a calendar year) to doctors and other health-care professionals by drug and medical device companies (back story).

Making public such information might make doctors think twice about accepting such large sums of money from the industry. Such disclosures would also make it harder for medical centers and federal agencies to ignore blatant financial conflicts, which, as I point out in my book, Side Effects, can spawn the publication of studies that are flawed and inaccurate. And finally, a payment registry would alert consumers to biases among doctors upon they rely for supposedly objective medical advice. As Grassley has said, “Making information about financial relationships open to scrutiny is the right thing to do.”

This landmark legislation was supposed to have been attached to a Medicare bill that passed this summer. In the process, however, it got watered down and then detached from the Medicare bill, says Dr. Peter Lurie, deputy director of the health research group at Public Citizen in Washington. He says the bill was altered to accommodate the concerns of the pharmaceutical industry and doctors’ groups.

Lurie notes, for example, that there’s a new clause in the bill pre-empting any state law that requires a similar public accounting of payments to doctors, as well as a new provision that delays the reporting of such payments for products under development.

“One could argue that those are precisely the kinds of conflicts we should be most interested in,” Lurie says.

Jill Kozeny, a spokeswoman for Sen. Grassley, said state law was pre-empted to ensure uniform nationwide reporting of financial conflicts. The provision to delay reporting for products under development was added to protect trade secret information. Drug companies had argued for the delay on grounds that they don’t want competitors to know what products they have under development.

Whether in its original or revised form, the bill isn’t going anywhere soon. As Lurie notes, “Congress is dealing with a few other pressing issues right now. Kozeny agrees. She says that "new legislation starting from scratch will be pursued by Sen. Grassley" in January. And it might actually have a chance of passage, Lurie predicts, especially if the country elects a Democratic president in November, along with more Democrats to the House and Senate.

Sunday, October 5, 2008

Conflict Allegations Force Dean of Academic Psychiatry to Step Down: Who's Next?

The academic kingpins who made so money at the trough of Big Pharma are starting to fall. This weekend, Charles Nemeroff stepped down from his post as chairman of Emory's Department of Psychiatry pending an investigation into allegations that he failed to fully disclose the millions of dollars he received in earnings from companies whose drugs he was simultaneously studying and promoting, according to The The Atlanta Journal-Constitution. Congressional investigators led by Senator Charles Grassley found that Nemeroff received $2.8 million in consulting fees from drug companies and failed to report a third of that amount to the university. If true, such failures to disclose would violate federal research rules and Emory's own ethics guidelines.

Nemeroff is just one of several prominent psychiatrists under investigation by the Senate Finance Committee. Others include Alan Schatzberg, chief of psychiatry at Stanford University), Martin Keller, (the psychiatry chief at Brown University) (back story here) and Karen Wagner (head of psychiatry at University of Texas Medical Brand at Galveston).

As Daniel Carlat says, Nemeroff is the creme de la creme of American psychiatrists. And his extensive ties to the drug industry go back for decades. In my book, Side Effects, I tell the story of how Nemeroff played a key role in quashing debate over the emerging suicidal side effects of Prozac and other SSRI antidepressants back as 1991. Indeed, some say it was his elegant presentation on behalf of Eli Lilly at the FDA's hearing that year that helped convince the FDA advisory panel to sweep concerns about the suicidal side effects of these antidepressants under the rug for another 13 years. At the 1991 FDA hearing, Nemeroff failed to disclose that he was earning lucrative consulting fees from Eli Lilly and even owned stock in the Indianapolis-based drug company.

While Nemeroff's conflicts of interest with Eli Lilly flew under the radar screen in the anything-goes decade of drug development in the 90s, Emory officials did raise concerns about his relationship with GlaxoSmithKline, the maker of Paxil, beginning in 2004. As first reported in The Wall Street Journal and The New York Times Friday, Congressional investigators found that between 2000 and 2006, Nemeroff was paid $960,000 by GlaxoSmithKline, yet he disclosed only $35,000 of those payments to Emory. During roughly the same period of time, Nemeroff was the chief investigator on a $3.9 million NIH study on five Glaxo drugs for the treatment of depression.

Yesterday, The The Atlanta Journal-Constitution reported that when Emory's conflict of interest committee first raised a red flag about the psychiatry chief's ties to Glaxo, he promised administrators in 2004 that he would earn less than $10,000 a year in drug company payments from then on. Yet according to documents entered into the Congressional record, Nemeroff went on to earn about $171,000 from Glaxo in 2004.

Emory officials seem finally to be losing patience with their doyen of psychiatry, who by the way brought in millions of dollars in research funding for the university (much as Martin Keller has done for Brown). In an interview with The Atlanta Journal-Constitution, a top Emory official said that "depending on the outcome of the university's own probe, the allegations could lead to the firing of Nemeroff."

Better late than never.

Sunday, September 28, 2008

Internal documents reveal extent of Paxil drug study chicanery

When I was a reporter for The Boston Globe in the 90s, an employee of Brown University's department of psychiatry handed me a raft of internal university documents. A number of these documents pertained to an ongoing clinical trial that compared the antidepressant Paxil to a placebo and older antidepresssant (imipramine) in the treatment of depression in adolescents. My book, Side Effects tells the story of how researchers at Brown University misrepresented data in this key clinical trial, known as study 329, so in the interest of transparency, I am posting these and other pertinent documents on my website.

The first document here is from the final GlaxoSmithKline report of study 329 (publicly available on its website), which shows that a 14-year-old boy who was in the Paxil arm of the study lost control, punching pictures, breaking glass and injuring himself in November 1994. He was hospitalized and seen as suicidal by the psychiatrists treating him. Yet this patient , known as #65 in the study, was not labeled as suicidal when the study was published in the July 2001 issue of the Journal of the American Academy of Child and Adolescent Psychiatry. (The following year, Paxil became the most widely prescribed antidepressant in the U.S.).

The second document here is a memo to Brown University's Institutional Review Board from Martin Keller, chief of psychiatry at Brown and principal investigator of study 329. In the memo, Keller reports that a teenager in the Paxil study was hospitalized in September 1995 due to becoming combative and suicidal. Yet in the memo, Keller says he has labeled this patient (#106) as noncompliant instead of suicidal as a result of taking Paxil. Likewise in the published 2001 study, this teenager is labeled noncomplaint and not included in the list of adolescents withdrawn from the study as the result of adverse side effects.

The third and perhaps most mysterious document is a memo from Keller to the IRBs at Brown and two of its affiliated hospitals, Butler and Bradley. In this January 30, 1995 memo, Keller reports that a teenage girl, patient #70 in study 329, ingested 82 Tylenol pills on January 19 and was hospitalized at St. Ann's Hospital. She was discontinued from the study at the end of January and coded as noncompliant according to another memo from Keller to Brown's IRB here. Yet according to the GlaxoSmithKline's final report, patient #70 in the same study was a 12-year-old boy enrolled in the trial on February, 22, 1995 and withdrawn on March 24 after suffering from chest pains. This patient had been randomized to the imipramine arm of study 329.

So the question remains: how did patient #70 go from being a teenage girl who overdosed on Tylenol to a 12-year-old boy with chest pains?

As I report in my book, Donna Howard, the former assistant administrator in Brown's department of psychiatry who gave me the internal Brown documents, said the data in study 329 was changed to satisfy the study's sponsor, SmithKline Beecham (which later merged with another company to become GlaxoSmithKline).

"Everybody knew we had to keep SmithKline happy and give them the results they wanted," Howard said. And she reiterated that comment last week when she was interviewed by Brown's own student newspaper, The Daily Herald.

In an editorial accompanying the news article, The Daily Herald editors raised the issue of why the university seemed to be judging faculty members by a different standard than it judges students who misrepresent or falsify data. Good question!

Tuesday, September 23, 2008

Student newspaper gives Brown a black eye

In June when the news broke that U.S. Senator Charles Grassley was probing the financial ties between Martin Keller, the chief of psychiatry at Brown University, and the drug industry, Brown officials tried to stonewall the entire issue. They refused to acknowledge that Grassley was seeking information from the university about whether Keller failed to fully disclose his myriad conflicts of interest with the very companies whose drugs he was studying and touting in medical journals and at conferences; see back story here.

Now, Brown's own student newspaper, the Brown Daily Herald, has leaped into the fray, with an indepth story on Keller and the problems with a key study of Paxil in adolescents, of which he was the principal investigator. The Herald cites my book, Side Effects: A Prosecutor, a Whistleblower and a Bestselling Antidepressant on Trial and research by Australian researchers, which both found the same thing: that Keller and his co-authors had misrepresented data in this clinical trial, known as study 329, that made Paxil look safer and more effective than it really is.

The student reporters who wrote The Herald story did their homework, reaching out to all the parties involved in this sordid tale, including Keller (who declined to talk), Donna Howard, the whistleblower whose inspiring story I chronicle in my book, and several Brown faculty members who remain baffled as to why Brown has taken no public action against Keller. They also quote university officials, who, true to form, said the university "can't discuss particular cases of possible claims of wrongdoing..."

Now that the cat's out of the bag at Brown, will they be more forthcoming? Stay tuned...

Wednesday, September 17, 2008

What the New York Times article on bipolar children didn't say...

I have to say I'm disappointed with the cover story on bipolar children in Sunday's New York Times magazine. The author, Jennifer Egan, raises the interesting question about why there has been such a sharp increase in the diagnosis of childhood bipolar disorder, but she fails to note a few salient facts, for instance, that this controversial diagnosis has been championed by psychiatrists who have earned millions of dollars in personal consulting fees from the very companies who make the anti-psychotic drugs used to treat this disorder.

Egan does throw in this line, "And of course, there are pressures and blandishments from the pharmaceutical industry, which stands to profit mightily from the expensive drugs -- often used in combination -- that are prescribed for bipolar illness, despite the fact that very few of these drugs have been approved for use in children." But a few paragraphs later, when she mentions Joseph Biederman, a psychiatrist at Massachusetts General Hospital and one of the fiercest proponents of using powerful drugs to treat young children for bipolar disorder, she neglects to mention that Biederman is being investigated by the Senate Finance Committee for failing to fully disclose that he earned at least 1.6 million dollars in personal income from the companies that make these expensive drugs.(back story).

That's a glaring omission in my view.

In her lengthy, 9,500-word article, Egan also fails to note the link between mania and the SSRI antidepressants, which I write about in my book, Side Effects: A Prosecutor, a Whistleblower and a Bestselling Antidepressant on Trial. Research has shown that in some children and adults, taking antidepressants like Prozac, Paxil and Zoloft, actually induces manic behavior. So the question becomes: which came first, the predisposition to bipolar disorder, which is accentuated by the use of antidepressants, or the drug-induced manic behavior, which then leads doctors to label as bipolar patients who are taking the drugs for depression?

Throughout the piece, Egan seems to favor a completely biological explanation for bipolar disorder. She fails to consider that in some children, the mood swings, hostility and irritability that are characteristic of a bipolar diagnosis, may have been caused or exacerbated by family issues, parenting difficulties, sibling rivalries, divorce, etc. Near the end of her opus, she briefly mentions that some bipolar children appear to get well as they get older, but instead of following that intriguing observation into what could have been an interesting examination of the interplay between nature and nurture, she swerves off into a discussion of the search for "biological markers" for bipolar disorder, as if it's just a matter of time till we find some.

It's almost as if Egan is willfully ignoring the published research here. Doesn't she know that scientists have tried for years to find biological markers for schizophrenia and similar disorders and failed? When it comes to mental illness, the answers are simply not as clear-cut as Egan would have us believe.

Wednesday, September 10, 2008

Can America's premier psychiatric assocation heal itself?

Judging by its response to the Senate Finance Committee, the leadership of the American Psychiatric Association (APA) still doesn't seem to get it. For the past several months, the Finance Committee has been investigating conflicts of interest between academic psychiatrists and the drug industry and in July, the committee widened its probe to include the APA, which represents most of the nation's psychiatrists; see (back story). Sen. Charles Grassley (R-Iowa), the ranking Republican on the Finance committee, demanded that the APA cough up detailed information about the revenue that the organization has received from drug companies since January 2003.

Grassley shone his spotlight on the APA shortly after the publication of my book, Side Effects, which reveals in detail the longstanding and mutually beneficial relationship that the APA has had over the years with the pharmaceutical industry. Beginning in the 1990s and continuing to the present, drug companies have paid the psychiatry profession’s trade association millions of dollars to sponsor industry symposiums at the APA’s annual meeting each year. Speakers at those well-attended symposiums often talk up drugs made by the same companies sponsoring their talks.

The conflicts that exist in the psychiatric community go far beyond that, of course. In Side Effects, I chronicle the millions of dollars that one academic psychiatrist, Martin Keller, chief of psychiatry at Brown University, was getting paid in consulting and speaking fees by the very drug companies whose drugs he was studying and touting in medical journals and at APA conferences. Keller is among the psychiatrists being probed by the Senate Finance Committee (back story). Another psychiatrist under Grassley's spotlight whom I also mention in my book is Alan Schatzberg, chief of psychiatry at Stanford University and president-elect of the APA (back story).

This past Monday, Nada Stotland, current president of the APA, wrote a long memo to the association's members explaining that the requested information was delivered to Sen. Grassley's office on Sept. 2, along with a letter explaining the revenue information. In her Sept. 8 memo, Stotland said the letter could be "accessed at APA's website by logging into the Members Corner and clicking on Grassley response." In other words, only paying members can access the letter, not to the general public. The APA's communications office has yet to respond to my request for a copy of the letter. Transparency this is not.

In her memo, Stotland makes it sound as though she's not exactly on board with the recent calls for reform. She writes, "Long traditions and established practices are not only being questioned, but also criticized across the board. Both the American Medical Association and the Association of American Medical Colleges have developed or are developing new standards that differ sharply from many decades of practice." It almost sounds like Stotland's problem is with the criticism of these longstanding practices, not the practices themselves.

Stotland does go on to say that well before Grassley's request (last March), the APA had put together several work groups to examine the extent of her organization's reliance on drug company funding and to establish guidelines for individual psychiatrists who take money from drug companies. However, the guidelines work group has yet to have their first conference call, according to Paul Appelbaum, director of the division of psychiatry, medicine and the law at Columbia University College of Physicians and Surgeons, who is chairing the latter group.

Appelbaum says he expects his group to examine the whole range of possible conflicts that emerge when psychiatrists are paid speaking and consulting fees by drug companies and given free meals, junkets and drug samples by company reps.

In his interview with me yesterday, Appelbaum sounded a less equivocal note than Stotland. "Merely because something has been a long-established practice is not justification for it to continue," he said. "I think in general we ought to be worried about money that flows from interested parties to researchers because it has the potential to alter their research findings and distort people's judgement."

It's good to see that somebody in a position of responsibility at the APA understands what's at stake here.

Wednesday, September 3, 2008

Antidepressants and Suicide Rates: Another Salvo in the Debate

Remember all those dire warnings from the psychiatric community that youth suicides would rise after the FDA put black box warnings on antidepressants in late 2004? The argument was that physicians would be scared away from prescribing these drugs for depressed youth, leading to a rise in suicide rates.

Well, guess what? The opposite seems to have happened.

Not only did the number of antidepressant prescriptions actually rise in 2005, according to a report from the U.S. Agency for Healthcare Research and Quality this summer. But a new analysis published this week in the Journal of the American Medical Association found that the rate of suicides among youth aged 10 to 19 years actually fell by 5.3 percent between 2004 and 2005 -- to 4.49 per 100,000 kids.

The authors of the JAMA research letter did note that overall youth suicide rates for both 2004 and 2005 were still greater than the rates in earlier years. But they declined to attribute the bump solely to the FDA boxed warnings. Indeed, they noted that a lot of other factors could be at work here -- alcohol use, access to firearms, the influence of online social networks and even suicides among U.S. troops.

And that is precisely what I concluded in an opinion piece I wrote for The Boston Globe a year ago. In that op-ed, I also noted that suicide rates have long been trotted out as a public relations tool by drug companies intent on selling antidepressants. Yet there is no evidence that the use of drugs such as Prozac, Paxil, Zoloft and Celexa contributed to a decline in youth suicide rates from 1995 to 2003. Indeed, as a number of epidemiologists have pointed out, suicide rates among children (and adults) were going down well before the new class of antidepressants (SSRIs) hit the market.

Conversely, there is no evidence of a link between the FDA black box warnings and the uptick in youth suicide rates in 2004 (which, as it turns out, occurred before the black warnings went into effect).

In the end, of course, such statistical navel-gazing doesn't mean much. As Julie Zito, associate professor of pharmacy and psychiatry at the University of Maryland, said in my book, Side Effects, "People who are specialists in statistics know you have to look at trends over years and years."

So until we have some long-term data to work with, we should take any new salvos in the debate over antidepressants and suicide rates -- pro or con -- with a healthy dose of skepticism. Especially since several authors of the latest analysis have received resesrch funding or consulting income from companies that make antidepressants.

Tuesday, August 19, 2008

A Valuable Window into the Drug Industry's Marketing Tactics

Critics of the pharmaceutical industry have long complained that drug companies resort to unscrupulous tactics to market their wares, handpicking friendly researchers (to whom they pay handsome consulting fees) for clinical trials, ghost-writing the results, and running studies for the express purpose of encouraging the adoption of new drugs. Such studies are known as "seeding" trials, and a new report in the current issue of the Annals of Internal Medicine reveals in disturbing detail how one company -- Merck -- paid for, ran and published such a seeding trial without bothering to tell the so-called authors of the study its true purpose: to encourage the use of Vioxx among primary care physicians. Indeed, as the editorial accompanying the report notes, "...deception is the key to a successful seeding trial. Institutional review boards, whose purpose is to protect humans who participate in research, would probably not likely approve an action that places patients in harms' way in order to influence physicians' prescribing habits."

As the Annals report notes, the seeding trial itself had little scientific merit. At the same time the it was launched, Merck was also starting the VIGOR trial to be the "definitive study of gastrointestinal toxicity." Interestingly enough, both the seeding trial, known as ADVANTAGE, and the VIGOR trial, uncovered the increased cardiac risk for Vioxx compared to naproxen, although as the world now knows, that risk was underestimated when the VIGOR study was first published in the New England Journal of Medicine in 2000.

The true purpose of the ADVANTAGE trial only became apparent because the extensive litigation around Vioxx unearthed internal Merck documents that showed the extent to which its marketing department had planned and run the whole shebang. As this and other cases illustrate, it is very difficult to get an inside view of drug company tactics short of a subpoena or official law enforcement request. Indeed, it took both to pry out of GlaxoSmithKline internal documents that showed the extent to which the pharmaceutical giant had tried to suppress negative results about the safety and effectiveness of its blockbuster antidepressant, Paxil.

As I reveal in Side Effects: A Prosecutor, a Whistleblower and a Bestselling Antidepressant on Trial, GlaxoSmithKline only gave up these damaging corporate documents after an official request from the New York Attorney General's office and a subpoena from lawyers representing the families of teenagers who killed themselves on Paxil or tried to. The resulting New York AG lawsuit essentially forced GlaxoSmithKline to post the results of all its clinical trials, negative as well as positive, on a publicly available website and led to other reforms as well. Yet such valuable "windows" into the drug industry could be closed if the US Supreme Court allows federal agencies to "pre-empt" state lawsuits against the drug industry. That is something none of us should wish for.

Tuesday, August 12, 2008

A flawed system of drug research, or why new drugs often do more harm than good

The August doldrums have settled in. Pharmalot is on vacation, as are most state and federal legislators. But there's a few items I'd like to take note of, since I too was on vacation when this news broke:

1. Stanford University finally saw the light and removed its chief of psychiatry, Alan Schatzberg, as principal investigator of an NIH study after Sen. Chuck Grassley continued to question Schatzberg's alleged conflicts of interest in the study. As you may recall from my previous blogs, Schatzberg owned $6 million in stock in Corcept at the same time that he was principal investigator of a study examining the effectiveness of Corcept's drug, RU-486, in treating psychotic depression. Grassley, a ranking member of the Senate Finance Committee, charged that Schatzberg failed to fully disclose his financial interests in Corcept to Stanford or the NIH, which is funding the RU-486 study. As Stanford said in its statement to the Senate Finance Committee, "having Dr. Schatzberg as the principle investigator on this grant can create an appearance of conflict of interest." Here's the letter Stanford sent to the NIH notifying them of its long overdue action.

2. Research reported at the annual meeting of the American Sociological Association echoes what I conclude in my book, Side Effects: A Prosecutor, a Whistleblower and a Bestselling Antidepressant on Trial: Americans are often exposed to unacceptable side effects because of flaws in the way new drugs are tested and marketed. Donald Light, a professor of comparative health policy at the University of Medicine and Dentistry of New Jersey, reported that two in every seven new drugs result in side effects serious enough for FDA action after the drugs have been approved, including black box warnings, adverse reaction warnings, or even withdrawal of the drug. Light also contended that drug makers design trials to minimize evidence of toxic side effects. For instance, they sample a healthier population of patients than those who will actually take the drug, excluding people who are older or have multiple health problems, according to GoozNews. Trials are also not run long enough to detect long-term side effects, Light says. In his talk, the sociologist noted that while current system of drug approval allows companies to boast that a drug is safe and effective, in reality, the label should read "apparently safe based on incomplete information..." Light concludes, as Side Effects does, that the FDA's sped-up drug reviews during the '90s and the first part of this century only led to significantly increased black box warnings and drug withdrawals after great harm was done.

Thursday, July 31, 2008

When will the NIH start enforcing its own conflict of interest regulations?

It looks as if the Food and Drug Administration is not the only federal agency in need of a Congress-initiated overhaul. The same Congressmen who recently vowed to strengthen the FDA's ability to levy fines against drug companies, order drug recalls and restrict drug industry advertising, according to The Wall Street Journal, are also investigating the failure of the National Institutes of Health (NIH) to monitor and take action against serious conflicts of interest among doctors who receive NIH funding for their research. Sen. Chuck Grassley, the ranking Republican on the Senate Finance Committee, recently issued a call for the NIH to revoke grants to academic scientists who fail to report financial conflicts of interest, according to The Chronicle of Higher Education.

The controversy attracting the most attention of late involves Dr. Alan Schatzberg, chair of psychiatry at Stanford University, who owns about $6 milion in stock in a company whose drug he is also studying. According to recent postings on Pharmalot and Health Care Renewal, Schatzberg failed to fully disclose the extent of his holdings in Corcept Therapeutics to either Stanford University or the NIH, which has been funding research by Schatzberg into the use of Corcept's drug, mifepristone (RU-486) for treating psychotic depression. While Stanford has defended its management of Schatzberg's conflict of interest by saying that the psychiatrist "has not been involved in managing or conducting any human subject research involving mifepristone," Dr. Bernard Carroll, writing in Health Care Renewal, points out that Schatzberg is the principal investigator of the mifepristone depression study and recently published a review extolling the effectiveness of the drug in treating depression. As Carroll says, "So here we have an NIH-funded principal investigator, with a clear conflict of interest, who supposedly remains at arm's length from the project, accessing the primary data files, running a new analysis himself, and publishing an exaggerated new efficacy result for his drug..."

Schatzberg, who is president-elect of the American Psychiatric Association, is also a buddy and long-time colleague of Dr. Martin Keller, the chief of psychiatry at Brown University, whose own conflicts of interest I expose in Side Effects: A Prosecutor, a Whistleblower and a Best-selling Antidepressant on Trial. Just like Schatzberg, Keller failed to fully disclose the extent of his financial conflicts to the NIH, which has awarded him millions of dollars in funding for research on depression. When I first wrote about Keller's conflicts in 1999 for The Boston Globe, the NIH said they would look into the matter. NIH officials took no action against Keller and now the question is: will the agency be similarly passive in the Schatzberg affair, even though its own grant policy from 1995 requires universities to disclose and avoid such financial conflicts? And will Congress step in if the NIH doesn't? Let's hope so.

Wednesday, July 23, 2008

The conflicts go on and on and on...

Health Affairs bills itself as "the number one cited health policy journal devoted to publishing original, peer-reviewed research and commentary." Judging by the journal's review of my book, Side Effects, its commentary may be original but it sure isn't unbiased. To review the book, Health Affairs turned to none other than Dr. Alan J. Gelenberg, a psychiatrist who is a long-time friend and collaborator of Dr. Martin Keller, the chief of psychiatry at Brown University whose financial ties to the drug industry I expose in my book. See Gelenberg's review here.

As a quick search of Medline reveals, Gelenberg, a professor of psychiatry at the University of Wisconsin, and Keller collaborated on at least 20 papers dating back to1989 and up to last year. Most of these studies involve the very antidepressants I write about in my book. Indeed, Gelenberg was a co-author with Keller on a notorious paper published in 1998 on the antidepressant Serzone, which occasioned an accompanying editorial by the editor of The New England Journal of Medicine titled "Is Academic Medicine for Sale?" because there were so many conflicts of interest between the researchers of this paper (Gelenberg and Keller included) and the pharmaceutical industry.

As Roy Poses points out in his Health Care Renewal blog, Gelenberg is a consultant to GlaxoSmithKline, the maker of Paxil (the bestselling antidepressant in the title of my book), Eli Lilly, Pfizer, Wyeth, Novartis and Forest Labs, all makers of other antidepressants. As for Serzone, it was pulled from the U.S. market in 2003 after it was found to cause liver damage and deaths in a number of patients.

Interestingly enough, on many of the studies that Keller and Gelenberg collaborated, a third author was none other than Dr. Alan Schatzberg, the head of psychiatry at Stanford University, who, like Keller, is currently being investigated by Sen. Chuck Grassley's Finance committee for his financial ties to the drug industry. See my July 4 blog.

Not surprisingly, Gelenberg failed to disclose these myriad conflicts of interest at the end of his review for Health Affairs. So the questions remain: did he disclose them to the editors of Health Affairs and what, if any, effort did they make to ensure that their reviewer was an unbiased source?

Sunday, July 20, 2008

The story behind the story

A few weeks ago, The Wall Street Journal reported that Sen. Chuck Grassley (R-Iowa) had asked the FDA to re-examine data it had received from GlaxoSmithKline (GSK) way back in 1989 when the drug company first applied for approval of its antidepressant, Paxil. Grassley alleged that GSK had misrepresented data in a study comparing the use of Paxil with placebo in treating adults with depression. See my June 15 blog, Drug company under fire for Paxil research.

In his June 12 letter to the FDA, Grassley also noted that this past spring, the British Medicine and Healthcare Products Regulatory Agency, FDA’s counterpart in the U.K., concluded that GlaxoSmithKline knew of Paxil’s increased suicidal risk in adolescents as far back as the 1990s but hid that information from physicians and consumers. I reach much the same conclusions in my book, Side Effects: A Prosecutor, a Whistleblower and a Bestselling Antidepresssant on Trial.

The attorney who reviewed my book for The Wall Street Journal must not have read about these new developments. Or perhaps he did but chose to overlook them. Indeed, there is much that Mark Hermann, an attorney who defends drug companies in product liability cases, overlooked or got flat wrong in his review, according to Dr. Roy Poses, a doctor affiliated with Brown University, who critiqued Hermann’s review in his latest Health Care Renewal blog. To the many fine points that Dr. Poses makes may I add that the point of my book is not that the drug industry funded the clinical trials of antidepressants, but that industry money paid for Paxil studies that are now being attacked as highly questionable in numerous quarters.

While some might argue that Hermann was only doing his job – after all, he gets paid to represent drug companies – the more salient question is: could The Wall Street Journal have found no one with a slightly less blaring conflict of interest to review my book? Surely, New York's bastion of business news can do better than this.

Monday, July 14, 2008

The Ties that Bind (Continued)

Senator Charles Grassley (R-Iowa) is now investigating Martin Keller, chief of psychiatry and the subject of my book,Side Effects: A Prosecutor, a Whistleblower and a Bestselling Antidepressant on Trial, according to Pharmalot.

I first wrote about Keller in a 1996 page-one article for The Boston Globe, revealing that his department at Brown had received hundreds of thousands of dollars from the Massachusetts Department of Mental Health for research that apparently wasn't being conducted. (Brown eventually returned more than $300,000 to Massachusetts state officials after they threatened to sue the university). In 1999, I published the news in The Boston Globe that Keller was earning hundreds of thousands of dollars from the very drug companies whose drugs he was studying and touting in medical journals.

My new book, Side Effects, chronicles the story of two women -- a prosecutor and a whistleblower -- who exposed the deception behind the making of the bestselling drug, Paxil. As it turns out, Keller was the principal investigator of a controversial study that was widely used to promote Paxil as safe and effective in adolescents. However, as Rose Firestein, a prosecutor for the New York State Attorney General's office, discovered, the actual data in this clinical trial showed that Paxil was no more effective than placebo in treating depression in adolescents and had far more severe side effects than the placebo did. Indeed, this particular study was one of three cited by the New York Attorney General in its landmark lawsuit accusing GlaxoSmithKline, the maker of Paxil, of “repeated and persistent fraud” in deceiving physicians and consumers about the safety and effectiveness of Paxil.

As Side Effects reveals, there is also evidence that Keller and his co-researchers misrepresented the data to make Paxil look safer than it really was. When I was researching the book, Brown said it was standing behind Keller and "the scientific integrity" of his research. Now that Congress is pointing its high beams at Brown's chief of psychiatry, I wonder if the university's tune will, finally, change.

The Ties that Bind…and Corrupt

In recent months, Senator Charles Grassley (R-Iowa) has shone a spotlight on the hundreds of thousands, in some cases, millions of dollars that drug companies have paid in speaking and consulting fees to prominent psychiatrists who failed to fully disclose these conflicts. Now, Grassley, a ranking member of the Senate Finance Committee, has widened his probe, investigating the American Psychiatric Association’s financial dealings with the pharmaceutical industry, according to Pharmalot and The New York Times.

As I reveal in my book, Side Effects: A Prosecutor, a Whistleblower and a Bestselling Antidepressant on Trial, the APA has long had a cozy and mutually beneficial relationship with the drug industry. Beginning in the 1990s and continuing to the present, drug companies have paid the psychiatry profession’s trade association millions of dollars to sponsor industry symposiums at the APA’s well-attended annual meeting each year. In Side Effects, I follow the trail of money that led to one such industry symposium, which was sponsored by a large pharmaceutical company whose hot new antidepressant was being studied and touted by the same psychiatrists it was paying to speak at this APA affair. The moderator of the talk was none other than Dr. Alan Schatzberg, president-elect of the APA, who is himself under investigation for his financial conflicts of interest; see
my July 4 blog.

Also chronicled in my book are the longstanding financial ties between the drug industry and the National Alliance for the Mentally Ill (NAMI), the most powerful advocacy group for people with mental illness in the U.S. Not only do drug companies contribute millions of dollars to NAMI’s coffers every year, but as I reveal in Side Effects, Jim McNulty, the president of NAMI from 2002 to 2004, was earning thousands of dollars in speaking fees from the very companies who made the antidepressants he was talking up in lectures around the country. Yet NAMI members had no idea that McNulty was anything other than an unbiased patient advocate, because he never bothered to disclose these conflicts.

Given such a sorry record of collusion, it’s nice to see Congress, at long last, looking into the dark dank corners of drug research.

Friday, July 4, 2008

Doctors under the Influence

Doctors on the take to drug companies seem to be dominating the news of late. Business Week recently chronicled the case of two doctors who touted the long-term use of Chantix and other prescription drugs to curb tobacco cravings in an Annals of Internal Medicine article. Turns out both doctors were being paid for speaking and consulting by the makers of these smoking cessation drugs, among them Pfizer, which makes Chantix. While Drs. Michael Steinberg and Jonathan Foulds disclosed these financial ties in the fine print at the end of the Annals article, they did not disclose their conflicts to the hundreds of patients they've steered to Chantix. (Reports that Chantix causes suicidal thoughts and behaviors in some patients are now being investigated by the FDA).

A day earlier, Pharmalot wrote about yet another prominent academic psychiatrist who failed to fully disclose financial conflicts of interest. The U.S. Senate Finance Committee discovered that Dr. Alan Schatzberg, chief of psychiatry at Stanford University, owns about $6 million in stocks in Corcept Therapeutics, whose drug is involved in a National Institutes of Health study that Schatzberg oversees. Sen. Charles Grassley (R-Iowa), a ranking member of the Senate committee, reported that Schatzberg failed to fully disclose the extent of his ties to Corcept Therapeutics. The psychiatrist also failed to fully disclose thousands of dollars in personal income from Johnson & Johnson and Eli Lilly in recent years. Here is Grassley's remarks about Schatzberg in the Congressional Record.

Schatzberg's ties to the drug industry go way back, as I reveal in my book, Side Effects: A Prosecutor, a Whistleblower and a Bestselling Antidepressant on Trial. In 1998, Schatzberg was the moderator of an industry-sponsored symposium that touted the benefits of a hot new antidepressant on the market, Serzone, manufactured by Bristol Myers Squibb. Schatzberg received money to moderate the symposium, as did several of the speakers that day, including Dr. Martin Keller, chief of psychiatry at Brown University, a major figure in my book. A few months after the symposium, Keller went on to publish a study in The New England Journal of Medicine touting the benefits of Serzone in treating chronic depression when prescribed with psychotherapy. For his services that year, Keller received $77,400 in consulting fees from Bristol Myers Squibb. The footnote? Serzone was removed from the market in 2004 after it was found to cause liver damage in patients, a number of whom died.

Friday, June 27, 2008

Book talk in Waltham July 1

For those of you interested in hearing more about my book Side Effects: A Prosecutor, a Whistleblower and a Bestselling Antidepressant on Trial, I will be giving a talk at Back Pages bookstore in Waltham on Tuesday, July 1 at 7 p.m.

This week, The New England Journal of Medicine gave the book a big thumb's up. (To read full review, go to Reviews). The reviewer, Dr. Richard Friedman, of Weill Cornell Medical College, wrote that Side Effects "used the case of Paxil to expose the unsavory and self-serving relationships among members of the pharmaceutical industry, psychiatrists, and members of the FDA" and that the book "has the brio of a crime thriller.” He concluded that this "riveting and well-researched account of these disturbing ties should be widely read by members of the medical profession, many of whom continue to believe, despite all evidence to the contrary, that they are immune to the influence of drug companies." Amen.

Monday, June 23, 2008

Pharmaceutical Giant under probe by Justice Department

GlaxoSmithKline is being investigated by the U.S. Department of Justice for its research and marketing of Paxil in both adults and children, according to the Wall Street Journal. US investigators are particularly interested in what Glaxo knew about the suicidal risks of Paxil when it sought approval for the drug with the FDA and when it promoted the drug for off-label use in children and adolescents.

The federal investigators were particularly interested in the Paxil clinical trial known as study 329, which is the focus of my book, Side Effects: A Prosecutor, a Whistleblower and a Bestselling Antidepressant on Trial. As Side Effects reveals, the authors of study 329 concluded that Paxil was safe and effective in adolescents, even though the actual data in the study showed the opposite. This particular study has come under fire from other independent medical researchers as well; see my previous blog Drug company under fire for Paxil research. Sen. Charles Grassley (R-Iowa) has also demanded an investigation of Paxil’s approval by the FDA.

Even as this controversy gains momentum, the drug industry is not standing idly by. Allan Lundy, a psychologist who receives research funding from the industry and has done antidepressant trials for several drug companies, wrote a largely negative review of my book – no surprise there. What is surprising is that a once respected newspaper, The Philadelphia Inquirer, published the review without questioning Lundy’s partiality. I guess this is what happens when economically squeezed newspapers cut their own book review staff and don’t vet freelancers' credentials.

Sunday, June 15, 2008

Drug company under fire for Paxil research

A perfect storm seems to be gathering over GlaxoSmithKline and research it funded to determine whether its antidepressant drug Paxil was effective in treating depression.

In March of this year, Australian researchers published an article in the International Journal of Risk and Safety in Medicine on one particular study of Paxil, known as study 329, that purported to show that the drug was more effective than a sugar pill or placebo in treating depression in adolescents. After re-examining raw data from the study, obtained from GlaxoSmithKline under subpoena, the IJRSM researchers instead concluded the data showed that Paxil was no more effective than placebo on all eight of the study’s pre-specified clinical outcome measures. They also found that after the study blind was broken, the researchers added a number of new outcome measures in order to show a statistically significant difference between Paxil and placebo. In other words, as the IJRSM paper concludes, the authors of study 329 manipulated the data. Shortly after this finding was published, Dr. David Egilman, a clinical associate professor at Brown University, filed an ethics complaint against Dr. Martin Keller, the principal investigator of study 329 and chief of psychiatry at Brown. Egilman says Brown’s provost wrote him a letter in May saying that the university reviewed the allegations against Keller, but declined to say what, if any, action it was taking against its long-time psychiatry head.

Likewise, in my book Side Effects: A Prosecutor, a Whistleblower and a Bestselling Antidepressant on Trial, due out Tuesday, I also reveal new information showing that Keller and his co-authors misrepresented data in study 329. In essence, Keller et al miscoded several teenagers as being noncompliant when in fact they were in fact suicidal, thus further skewing the results of this controversial study. Furthermore, as I show in my book, at the very same time Keller was touting study 329 as a positive finding for Paxil (even though the actual data showed the opposite), GlaxoSmithKline was paying him thousands of dollars in personal consulting income.

Finally, just last week, Senator Chuck Grassley (D-Iowa) released a report by Joseph Glenmullen, a Harvard psychiatry instructor, alleging that Glaxo researchers misrepresented data in an earlier study comparing the effectiveness of Paxil and placebo in treating depression in adults. In this 1989 clinical trial, which was used to gain FDA approval for Paxil, Glaxo counted as suicides in the placebo arm of the study, deaths that had actually occurred during the wash-out period of the study. The suicides, thus, occurred before the official start of the study and should not have been counted as placebo suicides, Glenmullen's report contends. Glenmullen prepared his analysis for a law firm who is suing GlaxoSmithKline, and he concludes that the wash-out suicides were included in the study to make Paxil look safer and more effective than it really was, according to The Wall Street Journal. The Journal quoted Glenmullen as saying, “Glaxo was aware of this risk and hid it.”

Taken together, all of this new evidence indicates that the real risk of suicidality from Paxil was far greater than its risk for patients on placebo. As Glenmullen notes in the Journal article, if the FDA had had the correct information back in 1991, when the agency first examined suicidal risks of the SSRI antidepressants, it might have issued warnings about these drugs then. Instead, the FDA didn’t require black box warnings about the suicidal effects of these drugs until 2004. And that raises the haunting question: How many young people’s lives were lost to suicide in the intervening 13 years?

Monday, June 9, 2008

Financial Conflicts between Doctors and Drug Companies Taint Research System

Senator Charles Grassley (R-Iowa) recently released records showing that a prominent psychiatrist whose work led to an exponential increase in the diagnosis of childhood bipolar disorder earned at least $1.6 million from the makers of drugs used to treat this very disorder. As The New York Times reported yesterday, Dr. Joseph Biederman, of Massachusetts General Hospital and Harvard Medical School, may have violated federal research rules by failing to disclose the extent of his payments from drug companies over the years.

Sadly, such blatant conflicts of interest are all too common. In a 1999 article in The Boston Globe, I wrote about another prominent psychiatrist, Dr. Martin Keller, chief of psychiatry at Brown University, who had earned more than a million dollars in 1997 and 1998 from the pharmaceutical industry, much of it from companies whose drugs he was studying and touting at conferences and in medical journals. In 1998, for instance, the same year that Keller published positive findings about Zoloft in the treatment of depression, Keller earned $218,000 in personal payments alone from Pfizer, the maker of Zoloft; he also received $77,400 from Bristol Myers Squibb, the maker of Serzone, the same year he was lead author on a positive study about Serzone, an antidepressant that has since been taken off the market because it causes liver failure. Keller, oddly enough, did not report any income from SmithKline Beecham on his 1998 return, a copy of which was obtained by The Globe.

It was not until I began researching my book Side Effects: A Prosecutor, a Whistleblower and a Bestselling Antidepressant on Trial that I discovered that Keller had indeed earned personal income from SmithKline Beecham (now GlaxoSmithKline), in 1998 as well as subsequent years. He admitted as much under oath in a deposition in a lawsuit against GlaxoSmithKline, the maker of the antidepressant Paxil, in September 2006. Why is this important? To begin with, Keller was the principal investigator of a major multi-center study of Paxil, which purported to conclude that Paxil was more effective than placebo in treating depression in adolescents. Just as with Biederman, Keller’s acceptance of money from the maker of a drug he was studying constitutes a blatant conflict of interest. And just like Biederman, Keller failed to disclose these conflicts to the federal agencies that were rewarding him millions of dollars in research grants. Equally important, if as Keller himself acknowledged under oath, he received payments from SmithKline in 1998, why didn’t that income appear on his 1998 tax return?

Tuesday, June 3, 2008

Time to Ban Drug Gifts and Rebates to Doctors?

The Boston Globe yesterday published my op-ed piece here about the extent to which drug companies run misleading ads and use rebates to essentially bribe doctors to prescribe their drugs. I received some interesting feedback, including an email from a lawyer who noted that the legal profession operates under ethical standards that forbid blatant conflicts of interest. He wondered why the ethical guidelines for doctors are more lax, which prompted me to investigate. And he's right: guidelines promulgated by the American Medical Association do not prohibit doctors and dialysis centers from taking substantial rebates on drug supplies they purchase from companies, or from accepting gifts, including meals and free lunches, from drug makers as long as the "gifts are related to the physician's work and are of minimal value (the AMA defines minimal value as gifts of $100 of less, which doesn't seem so minimal to me).

In addition, while doctors in this country are not permitted to own pharmacies, they are allowed to accept rebates and to own or have a financial interest in imaging labs or centers to which they can then refer patients. In an interview today, Dr. Daniel Carlat, a psychiatrist and author of The Carlat Psychiatry Blog, said he considers that "a conflict of interest since it gives doctors a financial incentive to over refer patients to these labs." The same principle is at work when doctors accept generous rebates based on the amount of drugs they prescribe.

As I note in my new book Side Effects: A Prosecutor, a Whistleblower and a Bestselling Antidepressant on Trial, research has shown that such largesse from drug makers can and does influence doctors' prescribing patterns. For that reason, the Massachusetts State Senate recently passed a bill banning any gifts from the pharmaceutical industry to doctors in the state. The bill is currently being considered by the state House of Representatives. If it becomes law, Massachsuetts would join Minnesota and Vermont in either banning gifts worth more than $50 or requiring public disclosure of such gifts, according to The Carlat Psychiatry Blog here .

Seems to me the AMA could do a lot more to discourage doctors from accepting gifts and rebates from the pharmaceutical industry. And so could our state and federal legislators.

Sunday, May 11, 2008

How Drug Advertising Misleads Consumers

Ever wonder why there are so many drug commercials on television these days? Because they work, despite the required litany of side effects in each ad. And now we know why these ads are so successful: new research indicates that viewers don't really absorb the risks of the drugs being advertised because the commercials are expressly designed to distract them from digesting this information.

Ruth Day and her colleagues at the Medical Cognition Lab at Duke University studied a series of drug commercials and found that drug advertisers employ a number of distracting tactics: they put the litany of risks in the middle of commercials when attention spans wander, they speed up the recitation of side effects, making it harder for listeners to digest the information, and they use visual effects to distract people from what they're hearing. In an ad for Nasonex, a nasal allergy drug, which features an animated bee, the wings of the bee moved and flashed during the side effects information. Yet when the benefits of the drug were enumerated, the bee hovered discreetly on one side.

"All these wing flaps and wing flashes and sparkly things esentially divided the attention of the viewers...and led to decreased knowledge" of the drug's side effects, said Day, who presented her findings at a recent Congressional Energy and Commerce hearing on direct to consumer advertising.

Day concluded that federal officials need to do a better job of ensuring that the treatment of risks and benefits are "balanced" in drug advertisements.

Other witnesses at the hearing, held by a House subcommittee on oversight and investigations, noted that drug companies do not have to obtain approval of the Food and Drug Administration for such direct to consumer ads and that the FDA reviews only a small portion of the advertising materials they receive (on a voluntary basis). The agency can issue a warning letter if they come across material that is misleading or deceptive, but last year, the FDA issued only two such letters, according to Dr. Marcia Crosse, director of health care for the U.S. General Accounting Office. She noted that the FDA's effort to police misleading ads slowed considerably after the agency began requiring that warning letters be routed through the FDA's chief counsel office, causing delays of up to six months.

"We found the effectiveness of the FDA in halting [false and deceptive] advertising is limited," Dr. Crosse said.

One solution would be for Congress give the FDA the authority and resources it needs to preclear all direct to consumer advertising, Crosse and other witnesses said. But that isn't going to happen any time soon, as the May 8 hearing made abundantly clear. Even as Rep. Bart Stupak (D-Michigan), chair of the oversight committee, talked about the need to strengthen regulations on direct to consumer advertising, other members of the same committee were busy pooh-poohing the need for more oversight.

"I wonder if this is the appropriate time to debate these issues," said Rep. John Shimkus, R-Illinois. Shimkus' skepticism was shared by four other Republican members of the committee, all of whom, as bloggers on Pharmalotpointed out, received thousands of dollars in contributions from drug companies in recent years.

So it looks like American consumers are going to continue to be distracted by bees who flap their wings at just the right moment during drug commercials.