February 16, 2007 Evelyn Pringle
n January 29, 2007, BBC-One broadcasted, “Secrets of the Drug Trials,” a Panorama program based on an investigation by reporter, Shelley Jofre, which revealed how GlaxoSmithKline misled doctors into prescribing Paxil off-label to children, even after its own clinical trials found that kids could become suicidal when taking the drug.
The program was one in a series involving the relatively new class of antidepressants known as the selective serotonin reuptake inhibitors (SSRIs), which have only been sold in the US for about 20 years.
Paxil is marketed under the name Seroxat in the UK. It has never been approved for use with children for any indication in either the US or the UK.
The first program, "Secrets of Seroxat," was aired in October 2002, and the feedback that followed was unprecedented, with 67,000 people contacting a BBC helpline and 1,500 people emailing Panorama with stories similar to those revealed in the broadcast. The second, "Emails from the Edge," was aired in April 2003, in large part due to the viewer's response from the first program.
Many of the documents in the latest program were obtained in a consumer fraud class action lawsuit filed in the US by the Baum Hedlund law firm alleging that the UK based GlaxoSmithKline suppressed information about Paxil's failed efficacy and increased risk of suicidality in children. The case is filed on the behalf of the general public defined as:
All persons or entities who purchased and/or paid for paroxetine under the trade name Paxil, Paxil CR and/or Paxil Oral Suspension in the states of California, Florida, Massachusetts, Nevada, New Jersey, Pennsylvania, Texas, and Washington for consumption by a minor.
Baum Hedlund, a US law firm handling antidepressant cases for more than 15 years, has reviewed thousands of documents and taken numerous depositions of Glaxo employees and medical professionals known as academic thought leaders, hired to promote Paxil over the years.
As usual, in lawsuits against drug companies, virtually every document produced in the litigation was stamped "confidential" by Glaxo and sealed under a court order. However, through a series of legal challenges, Baum Hedlund was able to get some of the documents released in part, by getting Glaxo to admit that many did not contain trade secrets and therefore should not have been sealed to begin with.
Baum Hedlund partner, and lead attorney on the case, Karen Barth-Menzies, appeared in “Secrets of the Drug Trials,” and provided many of the documents referred to by Ms Jofre in the program.
Paxil was hailed as a wonder drug in the 1990's, sold as an alternative to Prozac for treating depression in adults. But Glaxo was not satisfied with the profits from treating adults and wanted to gain a stronghold on the lucrative pediatric market.
According to Ms Menzies, under FDA rules at the time, if the company conducted tests on Paxil with children, Glaxo could get a 6-month extension on its patent, which meant enormous profits. To that end, hundreds of children were recruited from around the world for several pediatric studies with the largest conducted in the US, known as Study 329.
During the program, Ms Jofre interviewed Stephanie Gatchell who described how she had taken her daughter, Sharise, to a doctor because Sharise had not started her periods yet and was worried, at which time she was prescribed Paxil.
Although Paxil was also only approved for adults in Britain, the same as in the US, doctors are allowed to prescribe a drug off-label for an unapproved use if they believe it will help a patient. According to Panorama, at the time that Sharise was prescribed Paxil, around 7,000 children a year were on the drug in Britain.
Shortly after Sharise began taking Paxil, her mother noticed a dramatic change. "She became more confident," Stephanie said, "but with it came aggression and worse."
One day she noticed cut marks on Sharise's arm and realized that she was self-harming, "something she'd never ever done before," her mother said.
Stephanie convinced Sharise to stop taking Paxil but unbeknownst to her parents, she began taking the drug again without telling them. Not knowing she was on Paxil, her parents went away for a weekend and when they returned home, they found Sharise hanging from a loft with a suicide note laying next to a packet of Paxil.
According to Panorama, by the time of Sharise’s death, Glaxo had already tested Paxil on children six years earlier and the results showed that Paxil worked no better than a placebo, and in one study, 7 of the 93 children who took Paxil had to be taken to hospital and some kids in the study had self-harmed like Sharise.
Ms Menzies says, in her opinion, this should have been the time when Glaxo started warning doctors to stop prescribing Paxil to children, because it appears that the company knew then from more than one study, that it was ineffective and unsafe.
To verify this claim, during the program, Ms Jofre read from a non-confidential email dated October 14, 1998, written by the Paxil product director in the UK which stated: "The results of the studies were disappointing. The possibility of obtaining a safety statement from this data was considered but rejected."
In other words, Ms Jofre notes, Glaxo knew it could not get a license to treat children in the UK. She read another comment in the email that said: "The best which could have been achieved was a statement that although safety data was reassuring, efficacy had not been demonstrated."
"Consultation of the marketing teams confirmed that this would be unacceptable commercially," the email noted.
Back in October, 1998, another document labeled, “SB Confidential - For Internal Use Only,” clearly shows that Glaxo had decided not to try to get Paxil approved for children because studies found the drug ineffective and states: “Data from these 2 studies are insufficiently robust to support a label change and will therefore not be submitted to the regulatory authorities.” It further states:
Based on the current data from Studies 377 and 329, and following consultation with SB country regulatory and marketing groups, no regulatory submissions will be made to obtain either efficacy or safety statements relating to adolescent depression at this time.
The document also explains the rationale for not attempting to obtain a safety statement on Paxil at that time as follows:
i) regulatory agencies would not approve a statement indicating that there are no safety issues in adolescents, as this could be seen as promoting off-label use
ii) it would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine.
Although Study 329 was completed in 1998, it was first submitted for publication in mid-1999. It was a major step in the marketing plan to get the study published in a reputable medical journal because doctors look to journals for advice they can trust. "The first journal GSK tried rejected the article," Panorama reports, "so they tried another."
Because publishing the study in full would have resulted in a negative impact on Paxil profits, Glaxo decided to find other ways to market Paxil to kids. "Exit the doctors," Ms Jofre says, "enter the spin doctors" to help promote Paxil as safe and effective for teenagers.
"The inconvenient facts," she explained, "would be buried and the marketing people would spread the good news to doctors around the world."
According to Ms Menzies, Glaxo found ways "to blow up out of proportion the supposed benefits in Study 329 and downplayed the negative findings."
She explains that by using opinion leaders in the field, academics who everybody looks up to, doctors would be far more influenced to prescribe Paxil than they would be if approached by Glaxo salespersons.
At the time, the name of Dr Martin Keller, a professor of psychiatry at a prominent university in the US was apparently worth a lot to drug makers and specifically Glaxo. In a single year, Panorama reports, Dr Keller earned a half a million dollars from drug companies, including Glaxo.
Study 329 was finally published in the July 2001, Journal of the American Academy of Child and Adolescent Psychiatry, with Dr Keller’s name as the lead author, but his actual input was seriously questioned by Panorama. In one memo presented in the broadcast, Dr Keller thanked a ghost writer from a PR firm hired by Glaxo for preparing the manuscript stating: "You did a superb job with this. Thank you very much. It is excellent. Enclosed are some rather minor changes from me..."
Ms Jofre also read a letter from the ghost writer to Dr Keller, which informed him that all of the necessary materials were enclosed to enable Dr Keller to send the study to a journal for publication. The packet even included a cover letter to submit to the journal with instructions to Dr Keller stating: "please re-type on your letterhead. Revise if you wish."
Ms Jofre also demonstrated that it was clear that the PR woman was making crucial decisions about how to present the data from the study, by quoting one Glaxo executive as saying in a company document: "She's going too far in burying bad news."
"It seems incongruous that we state it as safe yet report so many serious adverse events," another internal Glaxo email dated July 19, 1999 states.
According to Panorama, there were actually 11 side-effects identified in the study including aggression, self-harm, and suicidal thoughts, but yet the final ghost written article read: "Of the 11 patients only headache (one patient) was considered to be related to the treatment," and concludes that Seroxat is "generally well tolerated and effective."
During the program, Ms Menzies told the audience: "They didn't tell the regulators or the physicians or parents about these risks or the lack of efficacy, instead they went out and promoted this specific study as remarkably effective and safe for kids."
"This was a drug that doctors were told could help prevent suicide," Ms Jofre pointed out, "when in reality it was actually making some children suicidal, a triumph of marketing over science."
Since Study 329, (Keller et al 2001), was published, it has drawn criticism from medical professionals around the world. One letter to the Editor by Professors, Dr Jon Jureidini and Dr Anne Tonkin, from Adelaide, Australia, stated: “We believe that the Keller et al. study shows evidence of distorted and unbalanced reporting that seems to have evaded the scrutiny of your editorial process.”
“Given that the research was paid for by Glaxo-Smith-Klein,” it reads, “it is tempting to explain the mode of reporting as an attempt to show the drug in the most favorable light.”
“Given the frequency with which it is cited in other scientific papers, at conferences and educational functions, and in advertising,” the letter notes, “this article may have contributed to the increased prescribing of SSRI medication to children and adolescents.”
“We believe it is a matter of importance to public health,” the letter concludes, “that you acknowledge the failings of this article, so that its findings can be more realistically appraised in decision-making about the use of SSRIs in children.”
Another highly critical editorial was published on June 12, 2004, in The Lancet, which stated in part that Glaxo “appears to be floundering in the semantic depths. While it has been earnestly parsing the meaning of ‘suicidal thinking and acts’ and ‘publicly,’ it appears to have forgotten what lies behind those words-people.”
To further ensure its ability to control negative information, Glaxo made investigators sign agreements not to disclose the study results without the company’s OK. “Those researchers, including myself, who did see results of negative paroxetine industry trials were prohibited by nondisclosure contracts from discussing them,” says Dr Jane Garland, Clinical Professor of Psychiatry, at the University of British Columbia, “Facing the evidence: antidepressant in children and adolescents,” in the February 17, 2004, Canadian Medical Association Journal. In the adolescent paroxetine trials she notes:
10.5% of patients discontinued paroxetine because of “serious” psychiatric adverse effects, of which the most common was euphemistically described as “emotional lability,” further defined as “suicidal ideation/gestures; conduct problems or hostility, e.g., aggressiveness….
“Such responses,” Dr Garland states, “led 7.5% of the outpatient participants prescribed paroxetine who initially were only mildly depressed to be admitted to hospital, while none of the placebo group required hospital admission.”
“The authors dismissed this result,” she says, “by stating that these psychiatric adverse effects were not attributed to the medication — despite the fact that numerous reports of agitation and suicidal behaviour in young people treated with SSRIs have accumulated since the 1990s.”
During the Panorama program, Ms Jofre interviewed SSRI expert, Professor Dr David Healy, of the North Wales Department of Psychological Medicine at the University of Wales, an academic who has long challenged SSRI makers. Dr. Healy is concerned that doctors were deceived into prescribing Paxil to children.
"We were all hoodwinked, misled, duped," he stated in the interview.
"If you'd heard the experts talk," Dr Healy said, "they all say the drug was extremely safe and very effective."
"They produce these clinical trials," he noted, "which appear to be evidence and they aren't, they're adverts."
In five studies, 329, 377, 701, 329-extension and 716, Glaxo coded suicidal thinking and acts, under “emotional lability.” In a recent paper titled, "Manufacturing Consensus," in Culture, Medicine and Psychiatry (2006), Dr Healy describes how regulators came to recognize the significance of the term “emotional lability,” stating:
As a result of a GlaxoSmithKline application to the regulators for a license for Paxil to treat childhood nervous disorders, the raw data from clinical trials were lodged with a number of national regulators.
Within a fortnight of seeing the raw data in response to queries as to the events behind the term emotional lability, in May 2003 the regulators in the United Kingdom issued a warning against the use of Paxil (Seroxat) for minors.
"A few weeks later,” Dr Healy reports, “GlaxoSmithKline wrote to all doctors noting that Paxil use was linked to suicidality and that withdrawal from Paxil was also linked to
an apparent doubling of the rate of suicidality."
In the Panorama program, Ms Jofre points out that Sharise Gatchell's doctor, "like thousands of others, prescribed Seroxat in good faith."
Stephanie discussed how she and Sharise watched the April 28, 2003, Panorama program together and how she had told her daughter, aren't "we lucky that you're off it," not realizing that Sharise was taking Paxil secretly.
Less than a month later, public health officials in the UK warned that Paxil should not be prescribed to anyone under 18, after reviewing the secret clinical trials that Glaxo finally turned over 2 years after the last study was completed.
The warning came 2 weeks too late for Sharise.
According to Ms Jofre, Glaxo refused to be interviewed for the program but issued a written statement saying the company rejects any suggestion that it improperly withheld trial data and that Paxil was never approved for children under 18.
Its statement seems to place the blame for off-label prescribing squarely on the doctors. "Any decision to prescribe a medicine outside its authorised indications, in the EU or the US," Glaxo wrote, "is made by a doctor on the basis of his/her clinical judgement and the interests of their patient."
However, this comment infers ignorance on Glaxo's part of the fact that Paxil was being prescribed off-label to children in massive numbers. In the US, the company knows exactly when Paxil is prescribed and by which doctor, because Glaxo pays a small fortune to purchase the detailed prescribing records for every physician in the US for use by sales representatives in targeting their customer-doctors.
One former sales representative recently said that she could see whether a perk such as a lunch she purchased for a doctor one week increased the sale of the drug that she was promoting simply by checking the prescribing records the next week.
The statement submitted to Panorama by Glaxo also states:
In the case of study 329 although a numerical difference in adverse events was observed by the company and the study's investigators, for patients taking Seroxat compared to placebo, these findings were not, by themselves, considered clinically meaningful due to the limited number of patients involved and the fact that suicidal thinking and behaviour is a recognised symptom of the underlying disease.
Critical experts say it is amazing to hear an SSRI maker still trying to blame suicidal thinking or behavior on the "recognised symptoms of the underlying disease," when it has long been stressed that if that were the case, the kids on a placebo would become suicidal instead of those on the medication.
According to Ms Jofre, this Paxil scandal shows how tightly the drug companies control medical research and Dr Healy agrees. "We're in a situation now," he says, "where people who are ill generally have been deeply betrayed by the whole process, deeply betrayed by the pharmaceutical companies and by all the experts that have been willing to actually lend their names to the process."
These so-called opinion leaders are basically unregulated loose canons. According to Dr Healy, "the role of a drug regulator is to regulate any claims a manufacturer might make as regards a new product in its advertising or detailing to doctors."
But they have no control over what academics say in lectures, medical journals or elsewhere and “no control over what assessments these academics might make in their roles as experts called on to contribute to an expert consensus on new versus older drugs," he says.
The European Medicines Agency (EMEA) alerted the FDA to the suicide risk in mid-2003. Glaxo did not. According to an internal June 2, 2003, FDA email provided to this author by Baum Hedlund, written by Dr Russell Katz to Dr Andrew Mosholder, the FDA had just learned about the increased suicide rate hidden under the term emotional lability and realized that Glaxo had pulled a fast one. Dr Katz stated in the email:
We have recently become aware of a presumed association between Paxil and suicidality in pediatric patients. We received a call from the EMEA a little over a week ago. A Dr. Raines told us that the company (GSK) had submitted data that demonstrated that use of Paxil in kids was associated with increased suicidality compared to placebo, and that the company proposed labeling changes.
I believe she also said that it was in the news, and it was a big issue. Tom and I told her that the company had not informed us of any of this, and we agreed to look into it.
“It turns out that the sponsor was in the process of submitting to us a partial response to a question we asked in the Approval letter for the pediatric use (you, you may recall, were the reviewer). Specifically, we had asked them to further elaborate the events subsumed under the preferred term ‘Emotional Lability’. Mr Katz further stated:
We received this partial response, and almost all of these events related to suicidality. The bottom line is that when data from the controlled trials in depression, OCD, and Social Anxiety are pooled, for “possible suicide related” events occurring during treatment or within 4 days after discontinuation, the rate is 0.14/patient-year on drug, and 0.05/patient-year on placebo, p=0.02.
“We have some problems with the methodology they used to capture cases,” he said, “but this is the major finding, and it has us worried.”
“The sponsor has not proposed labeling changes,” Dr Katz noted, “and makes a feeble attempt to dismiss the finding.”
“We want to move quickly to evaluate this signal,” he told Dr Mosholder.
“We are planning to look at the NDAs for other SSRIs,” he wrote, “to see whether or not similar events are being hidden by various inappropriate coding maneuvers, but we’d also like to compare the drugs in other meaningful ways if we can.”
“We also want to call the sponsor very soon,” he noted, “and ask some questions about their methodology.”
“Given your history, with this application and this general issue," Dr Katz told Dr Mosholder, "we think you would be the right person to help us think about the best way to approach the data in the other NDAs (and their sponsors), as well as to provide ideas for further sources of potentially relevant data and possible approaches to better evaluate this signal study (e.g., insurance claims databases, etc.).”
“Also, we’d like you to be in on the phone call, if possible,” he said.
In responding to the email, Dr Mosholder told Dr Katz: “As I recall, a number of the other SSRI pediatric supplements showed signals for behavioral adverse events. But these were mainly events such as agitation and hypomania, not self-injury (unless, as you suggest, they were similarly obscured by inappropriate terminology).”
A February 4, 2004, email from another highly paid Glaxo academic, Dr Neal Ryan, to fellow Study 329 authors, Dr Karen Wagner and Dr Keller, illustrates their alarm over the FDA’s order for drug companies to reevalute all SSRI studies. The email states:
FDA made each company go line by line through absolutely all documentation of all kids in all their studies. This is where 4 more subjects in our joint study fell out, unfortunately all the Paxil group. Don’t know severity or more information about this yet.
In a curious Glaxo email titled, “Study 329 Update,” to Dr Ryan, Dr Wagner and Dr Keller, the investigators who supposedly reviewed the data and authored the report, a GSK employee wrote:
We want to update you, as investigators on Study 329, about additional potential pediatric suicidality cases that were recently discovered. In a manual review of all SAE narratives and “trauma” cases, 10 additional events potentially suggestive of intentional self injury, suicidal ideation, or suicide attempt were identified. Four of the 10 events occurred in study 329, all in the paroxetine group. Consequently, this could potentially change the number of paroxetine suicide-related adverse events for that study from 6 to 10.
“These cases,” the email states, “included among those undergoing blinded review by Dr. Wagner, Dr. Ryan, and Dr. Apter for the pediatric suicidality manuscript.”
This message apparently caused Dr Ryan to panic because he was being contacted by reporters. In an email response he stated:
With your email yesterday (appended below) about 4 additional “events” in Study 329 on the Paxil arm, those of us involved in writing the recent letter to the reporter asking about details of our article need very very quickly to get absolutely as much information as you have and understand what part of this we need to pass on to her. Otherwise we are in the challenging position of sending her a good-faith effort at directly answering her questions that we find very shortly thereafter is no longer the most complete information available to us and which therefore might appear misleading.
“Can we get a much fuller explanation in email?” Dr Ryan asks. “Should we quickly set up a conference phone call?”
After viewing the Panorama program, Dr Fiona Godlee, Editor of the British Medical Journal, wrote an article stating: "Panorama's account of GlaxoSmithKline's successful attempts to market Seroxat for use in children, despite the fact that its own published trial found evidence of serious adverse effects and failed to show benefit, is fascinating but depressingly familiar."
"What is even more depressing," she notes, "is that such behaviour is still so widely tolerated within medicine."
"What is clearly wrong," Dr Godlee writes, "is writers, academics, or clinicians concealing under their coat tails an army of company spin doctors intent on distorting the scientific record."
As for what can be done to change what she refers to as "the blind-eye culture of medicine," Dr Godlee states: "In the interests of patients and professional integrity I suggest intolerance and exposure."
"And if journals discover authors who are guests on their own papers," she says, "they should report them to their institution, admonish them in the journal and probably retract the paper."
"Reputations for sale are reputations at risk," Dr Godlee concludes.
"We need to make that risk so high it's not worth taking," she states.
In the US, families bereaved due to Paxil suicides have joined together in lawsuits against Glaxo. During the BBC program, Ms Menzies described the tragic case of an 11year-old boy who was prescribed Paxil off-label and hung himself in a closet with the leash of his new puppy.
Stephanie Gatchell and her husband have moved away from the home that holds the pain of their daughter's suicide to try to begin a new life in Ireland, but say they cannot forgive Glaxo for hiding the truth about Paxil. "They just kept on denying and denying and denying," Stephanie said.
She notes that a program like Panorama virtually had to force Glaxo to admit the truth and says, "were they ever going to come out with the truth on their own? I don't think so."
"The decision makers in that company," Stephanie states, "should be brought to justice. They have a lot to explain."
Link to watch BBC’s Panorama “Secrets of the Drug Trials”: http://news.bbc.co.uk/2/hi/programmes/panorama/6291773.stm