Researchers call on journal to retract notorious Paxil study

The retraction of questionable scientific papers seems to be on the rise, due in large part to increased media scrutiny of scientific misconduct and conflicts of interest among researchers who fail to disclose they have skin in the game, i.e. lucrative financial ties to the drug and medical device companies whose products they are studying. Indeed, retractions are becoming so common that Ivan Oransky, executive editor of Reuters Health News, has started a popular new blog called Retraction Watch.

Sad to say, actual retractions may be the tip of the iceberg. Consider the 2001 study of Paxil in adolescents, the subject of my book, Side Effects. According to a recent article in the British Medical Journal, two academic researchers have called on the journal that published the Paxil trial, known as study 329, to retract it because of the way its authors manipulated and omitted data to make Paxil look safer and more effective in adolescents than it really was. As I reported in Side Effects and subsequent blogs, Dr. Martin Keller, then chief of psychiatry at Brown University and the lead author of this study, miscoded several teenagers who had become suicidal as a result of taking Paxil as being noncompliant instead of as developing adverse side effects from the drug. In addition, Keller and his co-authors concluded that Paxil was effective in treating depression when in fact the drug was not more effective than a placebo on either of the two primary outcome measures of the study and most of the original secondary outcome measures.

As the BMJ article notes:

The drug only produced a positive result when four new secondary outcome measures, which were introduced following the initial data analysis, were used instead. Fifteen other new secondary outcome measures failed to throw up positive results.

It is important to note here that Keller, along with most of the co-authors of this paper, had lucrative consulting or speaking arrangements with GlaxoSmithKline, the maker of Paxil, the full extent of which they failed to disclose when the paper was published. Indeed, as I reported in Side Effects, the 2001 paper itself was ghost-written by Scientific Therapeutics Information (STI), a medical company hired by GlaxoSmithKline and the same one that helped the former psychiatry kingpins Charles Nemeroff and Alan Schatzberg write an entire psychiatric textbook promoting Paxil, according to the New York Times.

Even though peer reviewers for the Journal of the American Academy of Child and Adolescent Psychiatry said that the results of study 329 did not show efficacy for Paxil and had a host of other methodological problems, the journal accepted the study for publication anyway. One wonders whether the fact that one of the co-authors, Dr. Graham Emslie, was on the journal's board at the time had anything to do with its precipitous publication in July 2001.

Before making the decision to put black box warnings about increased suicidal risk of Paxil and antidepressants in children and young adults in 2004, the FDA looked closely at study 329 and concluded that its conclusions were indeed misleading and did not demonstrate the drug's efficacy over placebo; read about this here.

Two academic researchers, Dr. Jon Jureidini,associate professor of psychiatry at the University of Adelaide, and Leemon McHenry, lecturer in philosophy at California State University, are now calling for the retraction of this study, which was used by Glaxo to heavily market Paxil to doctors treating depression in children and adolescents.

As the BMJ piece notes, the Committee on Publication Ethics (COPE) recently advised journal editors to retract a paper if “they have clear evidence that the findings are unreliable.” If any published paper fits this category, study 329 does.

Hat tip to Neuroskeptic for making me aware of the BMJ article.

Panelists to share tips on how to become a health and science blogger

On Wednesday, Jan. 19, I'm moderating a panel on blogging about health and science, sponsored by the New England Science Writers. We are fortunate to have attracted some top-notch bloggers, including Gary Schwitzer, whose HealthNewsReview blog was named the best medical blog of 2009 by Epocrates; Daniel Carlat, of the Carlat Psychiatry blog (who blogged about the upcoming panel here); Ivan Oransky, executive editor of Reuters Health News, who blogs at Embargo Watch and Retraction Watch; and Rachel Zimmerman, who curates the CommonHealth blog for WBUR radio.

It promises to be a very stimulating evening of conversation. You can learn more about the event at the NESW website. And you can follow Tweets from the event by following the Twitter hashtag #nesciblog11.

One more reason why Genzyme might want to resist Sanofi's overtures

For weeks now, The Boston Globe has been running stories about Sanofi Aventi's hostile bid to acquire Genzyme, the Boston-based biotech giant. One recent story talked about how the CEOs of both companies attended the same conference in San Francisco without talking to each other. Genzyme has repeatedly rebuffed Sanofi's offer largely on the grounds that the share price being offered is inadequate.

But here's another reason why Genzyme might want to be wary of Sanofi's overtures: its new CEO, Christopher Viehbacher, comes from GlaxoSmithKline, where as head of its US operations, he presided over some less than savory business decisions. He was, for example, at the helm when top Glaxo officials ignored problems with a production plant in Puerto Rico, according to a former Glaxo employee turned whistleblower. (Glaxo recently agreed to pay a $750 million fine and plead guilty to a felony for manufacturing fraud that led to untold bottles of contaminated meds, mislabeled packaging and incorrect dosages at this plant, according to Pharmalot.)

Viehbacher also headed up the company's US operations during the tempest over news that its anti-diabetes drug, Avandia, increased the risk of heart disease in patients. Even though a meta-analysis done by Dr. Steven Nissen, a cardiologist at the Cleveland Clinic, reported the increased heart risks in a major journal article in 2007, Glaxo executives kept insisting on the safety of their top-selling drug. It wasn't until an FDA advisory panel this past year recommended that Avandia either be pulled from the market or see its sales severely restricted that the company agreed to put black box warnings on the drug; read about this here. And Viehbacher was in charge when the New York State Attorney General's office sued GlaxoSmithKline for not telling doctors and consumers the full story about the suicidal risks of its blockbuster antidepressant, Paxil, and its lack of effectiveness in children and adolescents (which is the subject of Side Effects).

Viehbacher, of course, was not in charge in the late 1990s when company officials first decided to suppress data about Avandia and Paxil's risks. But since he became head of US operations in early 2003, there's a good chance that he was briefed about the dangers of these drugs and chose to do nothing about them, until forced to do so by regulatory officials. Indeed, according to the New York Times, after Nissen's study was published, Glaxo officials conceded that they had known of the drug’s potential heart attack risks for a number of years. But instead of pulling Avandia off the market, they reacted by defending the drug and threatening lawyers who were advertising on TV for patients who might have been harmed by taking Avandia; read about this here.

I have no idea whether Viehbacher was passed over for the top job at GlaxoSmithKline because of the less than ethical corporate behavior that occurred on his watch. But it is one more reason why Henri Termeer, the CEO of Genzyme, might want to think twice before handing over his company to Sanofi-Aventis.

More Americans harmed by prescription drug misuse than illegal drugs

Just last night, a friend of mine mentioned that an acquaintance of hers, a woman in her 50s who was taking prescription drugs for several conditions including diabetes and high blood pressure, died from an overdose of legally prescribed drugs. Which is why I was not surprised by today's story in the New York Times about new data showing that the number of emergency room visits in the U.S. from the misuse of prescription drugs has nearly doubled over the last five years. I was, however, surprised by the news that these prescription overdoses outstrip emergency care for people taking illegal drugs.

Perhaps we should all be shocked by such news -- shocked enough to do something about it. The reason for these latest statistics, which come from the Substance Abuse and Mental Health Services Administration, is obvious: the number of Americans taking prescription drugs has soared nearly 40 percent over the past 10 years and many of those people are imbibing multiple drugs, according to a Kaiser Foundation study. The impact on health care costs is well-known: spending on prescription drugs has doubled in the last decade, thanks in large part to the pharmaceutical industry's successful marketing of expensive drugs to a much wider segment of the American public than ever before.

We've also heard about the occasional celebrity who overdoses on legal drugs -- Heath Ledger and Brittany Murphy to name two, and I've blogged about the over-medicating of children with psychoactive drugs before; see here. But now we are seeing real evidence of the damage this pattern of overuse is wreaking on many people's lives.

There is no question that many health problems are treated or effectively managed through the use of prescription drugs and that some new drugs, particularly treatments for cancer and other diseases, are keeping people alive. But too many Americans are popping pills of questionable efficacy for conditions like high cholesterol, hypertension and depression. And because the drugs are "legally" prescribed by trusted medical professionals, consumers are much too sanguine about the side effects of these medications and how they interact with each other.

The best doctors closely monitor the drugs they prescribe to their patients and are very aware of possible drug interactions. The real danger comes when patients go to more than one doctor to get prescription drugs, a much too common occurrence. That, sadly, was the case with my friend's acquaintance: she had gotten her drugs from several caregivers and simply assumed they were safe.

The Times article today talks about a give-back program instituted by the Drug Enforcement Administration, where people have been able to drop off old or unused drugs at designated locations around the country. But I think health officials should be taking a more aggressive approach, perhaps by requiring patients to sign off with one primary caregiver before they fill their prescriptions. That's just one idea; I'll leave it to wiser heads than mine to come up with some workable solutions.

In the meantime, I hope the media keeps hammering home the message -- that just because the drugs you're taking are legally prescribed doesn't mean they're any safer than the drugs you might buy from the dealer down the street. If the latest finding is any indication, they can actually be more dangerous.

Six not-so-simple steps toward protecting people from dangerous drugs

Over the past two years there has been a steady diet of books and media reports about the disturbing influence the pharmaceutical industry has on medical research and doctors' prescribing patterns. Not a week goes by without a new report on the marketing muscle of the industry and the pervasive ties between the industry and the doctors upon whom we rely for supposedly objective medical advice.

A recent addition to this growing body of literature is The Risks of Prescription Drugs, which explains why the number of Americans taking prescription drugs has soared 72 percent in the last decade, with the result that an estimated 46 million Americans suffer from adverse side effects and 2.2 million are hospitalized every year. The book is co-written by five health policy experts and for the most part coalesces what has been written about in other places, including Marcia Angell's The Truth about Drug Companies, Jerome Kassirer's On the Take, Howard Brody's Hooked, Melody Petersen's Our Daily Meds, Peter Conrad's The Medicalization of Society and Side Effects, along with many newspaper reports.

However, The Risks of Prescription Drugs, published by Columbia University Press, does two things particularly well. First, it explains in a clear concise fashion why, despite the fact most new drugs offer little or additional benefit over existing meds, so many doctors prescribe these new drugs, exposing patients to serious side effects and adding billions in wasted costs to an already overburdened health care system.

Second, in the final chapter, the book offers comprehensive solutions to the problem, such as:

* Prohibit direct to consumer advertising by drug companies (because advertising to patients conveys inherently commercialized, biased information). Read more about this here.
* Create a stronger more independent Food and Drug Administration by more fully funding this federal agency so that it is no longer reliant on drug company user fees. (As reported in Side Effects, drug company money now accounts more than half of the FDA's entire drug-review budget.
* Change FDA policy so that new drugs are tested against existing drugs rather than against a placebo or sugar pill. (Right now, most drugs only need to show they are more effective than a placebo to win FDA approval).
* Reduce the commercial influence on doctors. While some medical schools such as Harvard have enacted strict policies prohibiting doctors from accepting free gifts, lunches and lucrative consulting and speaking deals from drug companies, too many others continue to allow such conflicts, all of which have been shown to bias doctors' judgment as researchers and clinicians).
* Get Big Pharma out of medical education. The Carlat Psychiatry blog makes a persuasive, ongoing case for why drug companies should not be allowed to fund continuing medical education.
* Limit the prescribing of unapproved uses of drugs, since such off-label uses are responsible for many of the adverse side effects seen in patients. See more about this here and here.
* Create and fund a new federal institute of medical science that can run clinical trials of new medications free of the drug industry's commercial interests. This institute could also be charged with doing objective research that compares the effectiveness of new products with existing drugs. As reported here, in the economic stimulus bill passed last year, President Obama included $1.1 billion for just this kind of comparative effectiveness research, but that should only be the beginning of a much larger, more comprehensive effort).

While all of these solutions are crucial if we want to improve our health care system and protect the public from dangerous and unnecessary drugs, the reality is that they will require the kind of political will that is in short supply on Capital Hill these days. That doesn't mean, however, that we should stop working toward such reforms. If anything, books like The Risk of Prescription Drugs are more important than ever -- in getting the truth out.

Mount Holyoke journalism class gains real-world experience

At the risk of tooting my own horn, I thought I'd post this video that was produced by Mount Holyoke College about the multimedia journalism class I teach there and our collaboration with the local newspaper, The Daily Hampshire Gazette. The video talks about how Mount Holyoke students are gaining real world journalism experience and helping a local newspaper gain a bigger footprint in its own community.

Government oversight agency calls on NIH to ban ghost-writing

Much has been written about the insidious practice of ghost-writing in medical research in this and other blogs and news articles. Even Dr. Francis Collins, the director of the National Institutes of Health (NIH), expressed dismay over the problem in a C-SPAN interview last year, calling it a threat to the "integrity of science." So far, however, not much has been done to curb such abuses.

In an open letter to the NIH yesterday, the Project on Government Oversight dialed up the pressure on Collins and the NIH by calling attention to several particularly egregious examples of ghost-writing. In the first, two psychiatrists, Dr. Charles Nemeroff and Dr. Alan Schatzberg, (whose ties to the pharmaceutical industry and conflicts of interest have been well-publicized) signed their names to a psychiatric textbook for primary care physicians that was in fact ghost-written by a contractor for SmithKline Beecham, now known as GlaxoSmithKline. As Duff Wilson reports in The New York Times, not only did SmithKline pay for the contractor to develop the outline and text for the two named authors but in emails obtained by PGO and the Times, the contractor also said it planned to show drafts and page proofs of the book to the drug company for sign off and final approval. Yet such company control was never disclosed in the textbook, which doesn't come as any particular surprise, since Nemeroff and Schatzberg have a history of failing to fully disclose their ties to the drug industry; see here.

Another ghostwriting example that the Program on Government Oversight highlights in its letter to NIH is one that I exposed in Side Effects: that a study of Paxil, spearheaded by Dr. Martin Keller, then chief of psychiatry at Brown University, was in fact ghost-written by the same contractor that ghost-wrote the psychiatric textbook mentioned above. According to documents that I obtained and posted here, this particular clinical trial, known as study 329, was skewed to downplay the suicidal risks of Paxil in adolescents and to make the drug seem more effective than it really was. According to email correspondence obtained by a law firm suing Glaxo, the contractor also sent this study to the drug company for final approval before it was published. In Side Effects, I quote an employee of Brown's department of psychiatry saying, “Everybody knew we had to keep [SmithKline] happy and give them the results they wanted."

While Keller has stepped down as chair of psychiatry at Brown, he remains a full professor there and is still receiving lucrative NIH grants. As the PGO letter notes, "Currently, [Keller] is the primary investigator on two NIH grants, with funding in 2010 of $1,341,493. Over the last five years, the NIH has given Dr. Keller $7 million in grants."

This is unacceptable. Keller has been accused of manipulating scientific data not only in my book but in scientific journals as well; see here and here. It's high time that the NIH stepped up to the plate and did as the Project on Government Oversight asked: "implement new policies that will require institutions to ban ghostwriting and make NIH funding contingent upon periodic certification from institutions that ghostwriting is strictly prohibited..."