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.
Friday, June 27, 2008
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.
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?
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?
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.
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.
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.
Thursday, April 17, 2008
Side Effects: Merck is not the first pharmaceutical company to use ghost-writers
An article in The New York Times a few days ago about Vioxx almost makes it sound as if the ghostwriting of new drug studies by pharmaceutical companies is a new and relatively unknown practice. In fact, the ghost-writing of research by pharmaceutical companies eager to publicize positive results about their new drugs in prestigious medical journals has been a widespread industry practice for years.
David Healy, a psychiatrist and professor at the University of Wales in England, was among the first to write about the practice of ghostwriting by drug makers a number of years ago. In several scholarly articles, Dr. Healy drew attention to the fact that Pfizer had ghost-written a series of positive research studies for its blockbuster antidepressant, Zoloft. In a review of internal Pfizer documents unsealed in lawsuits, Healy found that just as Merck did with Vioxx, a Pfizer was preparing a number of Zoloft studies for publication before they had identified authors for the studies. On an internal list of these in-process studies, Pfizer had put question marks next to the line for possible authors.
As my forthcoming book reveals, GlaxoSmithKline resorted to a similar scheme in its effort to publicize the results of a study purporting to show the effectivenes of Paxil in treating depression in adolescents. Unsealed documents from a lawsuit against GlaxoSmithKline show that a consultant for Glaxo ghost-wrote the first draft of this research and then sent it to the principal authors for review and approval. The Paxil study was rejected by JAMA(in large part because its positive conclusion about the antidepressant was not backed up by the actual data in the study), but the study was eventually published in the Journal of the American Academy of Child Psychiatry.
The article in the http://www.nytimes.com/2008/04/16/business/16vioxx.html?ex=1366084800&en=ef29a5f6ea0a6e76&ei=5124&partner=permalink&exprod=permalink" based its news on a recent study in JAMA that looked at documents unearthed in lawsuits over Vioxx, which was pulled from the market in 2004. As these documents show, Merck also hired ghostwriters to draft Vioxx research studies, then the company found prominent authors who would be willing to attach their names to the studies for publication in medical journals. As David Egilman, an associate professor in community health at Brown University, tells Pharmalot blogger Ed Silverman, “By having no outside researchers look at data or be in control of a study allowed Merck to manipulate the trials. They were able to use spin to create the impression that the drug didn’t kill people, which it did."
As Dr. Joseph S. Ross, the lead author of the JAMA article says, this practice raises broad questions about the validity of much published drug research. Indeed, I would argue that it raises questions about the credibility of the entire system of drug testing and research. And now, finally, the mainstream media is paying attention.
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