The Bitter Pill

The Official Blog of UNITE – uniteforlife.org

Glaxo Fights Against Public Paxil Trials

Evelyn Pringle April 8, 2008

Government attorneys appointed by the Bush Administration have been supporting GlaxoSmithKline in a number of courts across the country in an effort to convince the courts that lawsuits filed by victims of Paxil-induced injuries should be dismissed before ever making it to a jury.

In fact, the Administration has spent a massive amount of tax dollars filing amicus briefs on behalf of just about every drug maker involved in litigation in an attempt to get the lawsuits filed by private citizens thrown out of court.

The government claims that, once a drug and the warnings on its label are approved by the FDA, claims alleging injuries caused by a company’s failure to warn about a risk not listed on the label are preempted.

The Bush Administration says preemption applies even when a company (1) continues to sell a drug when a risk is known; (2) fails to warn when new risks are discovered; (3) fails to send letters notifying prescribing doctors of a known risk, and (4) fails to disclose a known risk to the FDA during the approval process, or anytime for that matter. In essence, if the FDA doesn’t make the companies warn, they’re off the hook.

If the Administration is successful in obtaining immunity for these drug companies, taxpayers will be left to pay not only the costs of medical care for all persons injured by drugs but also the life-long care for persons disabled by a product.

If Americans realized what was happening, there is no way they would approve of their tax dollars being spent to help the richest industry on the planet deprive fellow citizens of their right to a jury trial.

The typical brief against a plaintiff is filed by an army of government attorneys and will include an Assistant Attorney General, a Deputy Assistant Attorney General, a United States Attorney, an Assistant United States Attorney, two Appellate Attorneys from the Department of Justice, the FDA’s Chief Counsel, and the Deputy Chief Counsel, Associate Chief Counsel, and General Counsel for the Department of Health and Human Services.

Glaxo takes things one step further by submitting government amicus briefs that were filed in other cases (not just Paxil cases) and re-files them in virtually every one of the cases filed against the company in order to bolster its preemption arguments.

In O’Neal v GlaxoSmithKline, a case involving the suicide of a 13-year-old Sacramento, California boy, Benjamin Bratt, Glaxo recently used the Bush Administration’s preemption policy to argue that the child’s family should not be allowed to sue Glaxo for failing to warn about the suicide risk.

Benjamin committed suicide on February 14, 1997 by hanging himself. His parents, Terri O’Neal and Barry Bratt, filed a lawsuit alleging that, despite knowledge of suicide risks associated with Paxil prior to 1997, Glaxo concealed the information, failed to warn doctors, the medical community, and the public and all the while the company promoted the drug as safe and effective for children.

In the lawsuit, the Bratt Family alleged that Glaxo should have warned Benjamin’s doctor about the suicide risk both through the label and through other means, such as promotion, advertising, and “Dear Doctor” letters.

On January 30, 2008, federal judge, Frank Damrell, in the US District Court, Eastern District of California, dismissed the case and ruled that all of the family’s claims were preempted. The Bratt family has asked the court to reconsider the ruling. They believe the judge committed error in essentially holding that a drug that is not safe for adults is nonetheless safe for children until proven otherwise.

The family argues that adult clinical trials conducted by Glaxo as far back as 1989 showed an 8 times increased risk of suicidal behavior for Paxil users compared to patients receiving a placebo, but that Glaxo manipulated the data to obscure the risk, and then published the false data in medical journals and articles throughout the 1990’s.

In his ruling, Judge Damrell held that, even if GSK had clinical trial data prior to 1997 that showed an increased risk of suicidality in adults, that data was not sufficient to prove the risk extended to children using Paxil.

The Court held that, because the first clinical trial of Paxil with children did not conclude until 1998, Glaxo could not have known about the suicide risks with kids before that date.

During the January 18, 2008 oral argument on the preemption motion, Judge Damrell himself pointed out that a finding of an increased risk of suicidality in adults would logically apply to children. He specifically stated:

“As a practical matter, if I see there was an association of suicide ideation with anybody and enough of it, the last person I want to see using it is a child. That may not be scientific, but I’m just talking as a grandfather and human being.”

However, in his order, Judge Damrell seems to say the exact opposite:

“That later clinical studies ultimately led to a clear signal of pediatric suicidality, and that these studies arguably reflected the initial data in 1989 and 1991 of similar associations among adults, simply does not provide ‘reasonable evidence’ of the association of pediatric suicidality in February 1997.”

“It is difficult to reconcile Judge Damrell’s statements during oral argument with his ruling,” says senior trial attorney, Ron Goldman of Baum, Hedlund, Aristei & Goldman, the law firm representing the Bratt family.

Baum Hedlund has roughly 30 lawsuits on file involving Paxil-induced suicides and suicide attempts. Over the past 18 years, the firm has handled more than 3,000 cases involving antidepressants, including Glaxo’s Paxil, Eli Lilly’s Prozac and Pfizer’s Zoloft.

The first study Glaxo conducted on children was called Study 329. The study was started in 1994, three years prior to Benjamin’s suicide, and was completed in 1998, nine months after his suicide.

Judge Damrell bought Glaxo’s argument that, because Study 329 wasn’t completed until after Ben Bratt’s death, the company could not have warned of a risk in children prior to that. But, during the four years the study was ongoing, Glaxo received numerous reports of suicidal behavior occurring in children taking Paxil.

Coupled with the risk evident from the adult clinical trials since 1989, the Bratt family argues that Glaxo could have and should have warned of the risk for all people taking the drug long before Benjamin ingested Paxil.

Coincidentally, when the study 329 was finally published, the authors stated that, “The adverse-effect profile of paroxetine in this adolescent population was concordant with that reported in studies of adult patients with depression.”

The Bratt family argues that, the question of whether reasonable evidence of an association existed between Paxil and suicidality in any population at the time of Benjamin’s death is one for the jury.

The question of what Glaxo knew and when Glaxo knew it is also a question for the jury. Glaxo’s attempt to continue the parade down this rabbit trail is simply an attempt to divert attention away from the core issue here. The decisive question in a preemption context for the Court to determine is, “was GSK ever prohibited by the FDA from issuing a warning” thus creating a direct and positive conflict. The answer is unequivocally “NO.”

Judge Damrell also held that, if Glaxo had warned about a suicide risk for kids prior to 1997, such a warning would have been subject to a misbranding action by the FDA.

According to Mr Goldman, “Under no circumstances, given the regulatory scheme, can a drug be considered ‘misbranded’ if the science supports a truthful warning of the risk of suicidality.”

“Under the law,” he says, “it is a drug manufacturer’s duty to warn of risks known or reasonably scientifically knowable.”

“A drug company that fails or refuses to conduct necessary analyses in a scientifically acceptable manner,” he states, “shirks its legal, not to mention ethical and moral, duty to the medical profession and the public.”

According to the US Supreme Court, preemption applies (1) where it is impossible for a private party to comply with both federal and state law; and (2) where the state law stands as an obstacle to the accomplishment and execution of the full purposes and objective of Congress.

“When carefully analyzed, there is absolutely no evidence showing that it would have been ‘impossible’ for Glaxo to warn of this very serious risk, an absolute requirement in cases where conflict preemption is raised,” Mr Goldman contends.

“To the contrary,” he says, “such a warning is in perfect harmony with the FDA regulations and the overarching purpose of the FDA: to promote health and safety in prescription drugs.”

In their brief filed in opposition to summary judgment, the Bratt Family stated: “GSK would like to convince this Court that it is merely a ‘puppet’ when it comes to labeling its multi-billion dollar blockbuster drug, Paxil.”

“According to GSK,” the brief notes, “it is hapless and at the mercy of the FDA when it comes to the content of Paxil’s label.”

Glaxo claims it needed the FDA’s prior approval to issue a warning. However, the attorneys in the Paxil cases point out that Glaxo itself changed the label and sent out a Dear Doctor letter warning about the suicide risk in May 2006, with no prior approval from the FDA. The FDA never objected to the letter or the strengthened warning label.

The FDA, in its amicus briefs, has asserted twisted logic in these cases because the FDA cannot force a company to add a warning to a label. On March 1, 2005, the FDA’s deputy director for the Office of New Drugs, Dr Sandra Kweder, testified at a hearing before the Senate Committee on Health, Education, Labor and Pensions, that the FDA does not have the authority to require a specific label change and that the agency has to negotiate with the companies about how things should be worded, placement, those kinds of things.

During oral argument in SSRI suicide cases, industry attorneys claim that the reevaluation of the suicide risk of all the pediatric studies on SSRIs occurred after Glaxo “voluntarily” offered up the studies to the FDA.

For instance, on December 10, 2007, during oral argument in a case in a federal court in Philadelphia, a Pfizer attorney, Malcolm Wheeler was asked by the court: “What was the tipping point then for the change in position with respect to adolescents and then later extending that to young adults up to age 24?”

Mr Wheeler replied: “The tipping point was because GlaxoSmithKline voluntarily went forward and informed the FDA of some study results and said here are these results.”

“And what the FDA did as a result of that,” he told the court, “was to conduct a new analysis, pooling the data from nine different drugs, not just SSRIs, but nine different antidepressants, to say when we pool all the data from these various antidepressants, does it indicate any signal that suggests that we ought to do something other than what we’ve done in the past?”

However, that is a gross misrepresentation of what actually happened. The truth is, according to FDA documents obtained in litigation, that the European Medicines Agency (EMEA) contacted the FDA in mid-2003 to alert officials about the hidden suicide risk in the pediatric Paxil studies.

According to a June 2, 2003, FDA email written by Dr Russell Katz to Dr Andrew Mosholder, the FDA was notified in May 2003, that suicide events were hidden under the term “emotional lability.” Dr Katz’s email states:

“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.”

Dr Katz told Dr Mosholder that the FDA had asked Glaxo to elaborate on the events listed under the term emotional lability and 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, but this is the major finding, and it has us worried,” he wrote.

“We are planning to look at the NDAs for other SSRIs 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,” Dr Katz informed Dr Mosholder.

A report by Harvard psychiatrist, Dr Joseph Glenmullen, retained by Baum Hedlund as an expert witness in the Bratt case shows that Glaxo knew as early as 1989 that patients who received Paxil in clinical trials showed an 8-fold increased risk of suicidality compared to patients who received placebos. Dr Glenmullen’s report was initially filed under seal, however, on January 30, 2008, the majority of the report was unsealed.

In the report, Dr Glenmullen also notes that, when Glaxo coded suicidal behavior in its computerized database, most of the suicides and suicide attempts were coded as “emotional lability,” which he says is “a technical term for rapid mood swings, for example from crying to laughing.”

Another claim consistently made by both the Bush Administration attorneys and the attorneys for the SSRI makers, is that the FDA’s failure to make the companies issue warnings somehow means the FDA considered and rejected offers by the companies to add warnings about the suicidality risk.

However, Dr Katz specifically notes in his email that Glaxo never offered to add a warning to the label in the US, even after the FDA became aware of the increased suicide risk and discussed the issue with Glaxo.

“The sponsor has not proposed labeling changes and makes a feeble attempt to dismiss the finding,” he told Dr Mosholder in the email.

In the first SSRI case where preemption was raised (the company lost the argument), Motus v Pfizer, the judge wisely observed that, “although the FDA did not require Pfizer to include suicide-related warnings in Zoloft’s label, FDA has not prohibited Pfizer from doing so” and the “FDA never stated that it would be impermissible to include additional warnings.” Likewise, because Glaxo never sought to add a suicide warning, it is not possible that the FDA considered and a suicide warning.

On June 10, 2003, the UK’s Medicines and Healthcare Products Regulatory Agency issued the warning: “It has become clear that the benefits of Seroxat in children for the treatment of depressive illness do not outweigh these risks.”

In the June 11, 2003 New York Times, Gardiner Harris reported that Alan Metz, the vice president for clinical development at Glaxo, said the company was not warning American doctors against using the drug with depressed children in the US.

Dr Metz acknowledged that Paxil was not approved for treating children in the US but that many doctors prescribed the drug for children anyway. Mr Harris pointed out that Glaxo had applied for approval from the FDA to sell Paxil to children with obsessive compulsive disorder and the application was pending at that time.

On June 20, 2003, the Times reported that the FDA’s reanalysis found that the risk of suicidal thoughts and suicide attempts was 3 times greater among children using Paxil, mostly teenagers, than among children given placebos.

On August 12, 2003, the Times ran a commentary by Richard Friedman, a psychiatrist and director of the psychopharmacology clinic at Weill Medical College of Cornell University, which stated in part:

“What is disturbing about the recent report is that the purported link between Paxil and suicidal thinking comes from an unpublished study sponsored by Paxil’s manufacturer, GlaxoSmithKline.”

“In fact, GlaxoSmithKline has published only one of its nine studies of Paxil in children and adolescents to date,” he reported.

In its preemption motion, Glaxo offered nothing to support the claim that the FDA had considered, much less rejected, a proposal to add a warning about the increased suicide risk for kids. In fact, the studies in question were not submitted to the FDA until 2002, when Glaxo sought approval for new uses of Paxil, meaning it would have been impossible for the FDA to have considered whether a warning was appropriate based on a risk known only to Glaxo.

To support their argument that the FDA had never rejected a Glaxo proposed warning, the Bratt family brief states: “None of the GSK employees in the past 14 years who have, or had, responsibility for communicating with the FDA regarding Paxil could point to any specific, proposed suicide or suicidality language that was rejected by the FDA.

In his report, Dr Glenmullen explains how Glaxo successfully avoided having to include a warning on the label when it obtained FDA approval for Paxil in 1992:

“GlaxoSmithKline’s ‘bad’ Paxil data made it look as if patients randomized to Paxil were no more likely to become seriously suicidal when, in fact, the correct data shows patients on Paxil were eight times more likely to commit or attempt suicide.”

“One again,” he states, “GlaxoSmithKline’s ‘bad’ Paxil numbers carried the day: The FDA approved Paxil on December 29, 1992 with no warning to doctors or patients of the significant increased risk of suicidal behavior.”

The FDA’s Dr David Graham, most famous for exposing the risks associated with Vioxx, says the government’s attempts to immunize drug companies must not succeed. In an August 30, 2005 interview with Manette Loudon, the lead investigator for Dr Gary Null, (author of numerous books including “7 Steps To Overcoming Anxiety and Depression”), Dr Graham was asked about his views on attempts to pass tort reform.

“I think it’s dangerous and wrong,” he stated. “We already have an FDA that’s been neutralized by industry and sees industry as its client.”

Dr Graham said the agency is not going to protect the average citizen from the consequences of unsafe drugs, so the only alternative is the legal system. “That’s the only way we have of getting companies to change their behavior,” he said and, “tort reform would remove that threat as well.”

“It’s basically giving companies immunity because now the people who are injured by the drugs can’t recover damages that might actually mean something to industry,” he advised.

“I mean $250,000 for damages; they blow that in one ad campaign,” he stated. “To them, that’s nothing.”

“But a lawsuit for multiple millions of dollars has more of an impact,” he added.

“Now, is that optimal?” he said. “No.”

“But the fact is that since we have a regulatory agency that doesn’t regulate and we have a public health agency that doesn’t protect the public, we have thousands of people who are being injured by products that the FDA knows are unsafe,” he told Ms Loudon.

He pointed out that the FDA knew there was a big problem with Vioxx in mid 2000, and did nothing about it. If the FDA is not going to exercise control over companies, he said, there has to be a system in place “that reins companies in.”

In addition to the agency’s failure to protect the public against Vioxx, Dr Graham also discussed the FDA’s attempts to conceal the increased suicide risks that were found in the reevaluation of the pediatric SSRI studies in early 2004. “The FDA had suppressed a report written by a colleague of mine in drug safety and had prevented him from presenting this information in an advisory committee meeting,” he explained.

“That information leaked to the media,” Dr Graham continued, “embarrassing the FDA because it had been caught suppressing very important information – that most of the antidepressants don’t work for treating children.”

He told Ms Loudon that someone in his supervisory chain at the FDA even initiated a criminal investigation to identify the person who had leaked the information to the media.

With the SSRIs, he says, the FDA should have insisted on a signed informed consent form, that said three things: (1) these are the antidepressants available and only Prozac has been shown to work for children; (2) all the other drugs are no better than placebos; and (3) all these drugs appear to have the ability to increase the risk of suicidal behavior.

As a parent, he stated, if I saw that in writing and the doctor was going to write the prescription for some drug other than Prozac, I could say, “Doc, why are you putting my child on a drug that doesn’t work in kids.”

According to Dr Graham, the FDA did not want patients to have that information, so it refused to require signed informed consent. And, the companies didn’t want parents to have that information because all of a sudden the lucrative “off-label” use of the drugs would have dried up.

Dr Graham also explained that, if the FDA pulls a drug off the market due to safety issues, it not only hurts the marketing of the drug, but also calls into question why it was approved in the first place.

“Therefore,” he said, “you get this culture of cover-up, this culture of suppression, this culture of denial, and this culture that demonstrates above all else that industry is the client and not the American people.”

Most Americans do not realize that a preemption decision on whether to throw out a lawsuit largely hinges on the judge assigned to the case. Attorneys James Beck and Mark Herrmann run the “Drug and Device Law” blog and they post their personal views on topics that arise in the defense of pharmaceutical company product liability litigation.

On May 17, 2007, they posted a piece called, “Picking Spots In Preemption Cases.” The bloggers lamented that “two adverse preemption decisions over the last couple of weeks [ ] have us scratching our heads.”

The opinions referred to were Barnhill v Teva Pharmaceuticals, No 06-0282, (SD Ala Apr 24, 2007), and Kelly v Wyeth, 2007 WL 1302589 (Mass Super Apr 12, 2007).

In their blog, Mr Beck and Mr Herrmann discuss the importance of filing preemption motions with judges who are already known to be unsympathetic to private plaintiffs who sue drug companies.

“With respect to Kelly,” they state, “the most salient point for us is why a preemption motion was brought at all in a state trial court in Massachusetts – a known pro-plaintiff jurisdiction.”

“There’s certainly no history of success with preemption motions in prescription medical product cases in Massachusetts,” they point out.

“Part of preemption strategy is choosing the jurisdictions in which such motions would have a reasonable likelihood of success,” they explain.

“In plain English, you gotta pick your spots,” the attorneys advise.

“If defendants go running helter skelter into courts filing preemption motions no matter how hostile the jurisdiction – well, the result is going to be decisions like Kelly,” they warn.

“That doesn’t do the filing defendant any good,” they state. “Nor does it do anyone else defending prescription drug cases any good.”

On the other hand, in the September 2007 paper, “The Truth about Torts: Using Agency Preemption to Undercut Consumer Health and Safety,” legal scholars, William Funk, Sidney Shapiro, David Vladeck and Karen Sokol, of the Center for Progressive Reform, discuss the importance of jury trials, and the tort system in general.

“It is less susceptible to disproportionate influence by large companies and trade associations than the federal regulatory system,” they note and explain:

“When agencies respond to such influence by failing to regulate, or by adopting inappropriately weak regulations, the tort system becomes the primary legal vehicle for consumers to obtain protection from dangerous products and services.”

“Because tort decisions are made by juries, and because plaintiffs’ lawyers have the necessary skill and incentives to seek appropriate levels of protection for consumers and patients, the civil justice system puts individual consumers on the same footing as large corporations,” according to the paper.

“Unlike the regulatory system,” the authors explain, “the civil justice system makes it possible for members of the general public to be directly involved in governing.”

“This is a crucial distinction,” they note, “since individuals normally lack the same incentives as politically appointed government officials to resolve regulatory problems in favor of regulated entities.”

They also note that, “although corporate interests expend significant resources in an attempt to populate the judiciary with industry-friendly judges in states where judges are elected, there is simply no way to ‘capture’ all the judges throughout the country’s numerous state and federal, trial and appellate courts.”

“Moreover, even where judges are elected, citizens serving on juries are responsible for making decisions about liability,” the paper concludes.

(Written as part of the SSRI Antidepressant Litigation Monthly Round-Up, Sponsored by Baum, Hedlund, Aristei & Goldmans’ Pharmaceutical Antidepressant Litigation Department)

Filed under: 2008, Baum, Fraud, Glaxo, Graham, Paxil, Preemption, suicide

Lawmakers Catch Glaxo Hiding Paxil Suicide Risks – Again (Part I)

Evelyn Pringle February 12, 2008

GlaxoSmithKline recently received greetings from a Congressional Committee, asking the company to explain the findings in a report unsealed last month in a lawsuit which shows that Glaxo knew as early as 1989 that Paxil increased the risk of suicidal behavior in patients by more than 8-fold compared to patients who received a placebo.

In a February 6, 2008 letter, Senator Charles Grassley (R-Iowa), ranking member of the Senate Finance Committee, is asking Glaxo to explain why the American public was never adequately informed of this risk until May 2006 in a “Dear Healthcare Professional” letter which reported a “higher frequency of suicidal behavior” associated with Paxil as compared to placebo.

The report showing the 8-fold suicide risk, by Harvard instructor and psychiatrist Joseph Glenmullen, was unsealed on January 18, 2008, by a federal judge in a US District Court in Sacramento, California in the Paxil suicide case of O’Neal v SmithKline Beecham d/b/a GlaxoSmithKline, filed by the surviving family members of 13-year-old Benjamin Bratt.

Dr Glenmullen was retained as an expert in the case by the California-based Baum, Hedlund, Aristei & Goldman law firm.

On January 30, 2008, the court dismissed the lawsuit on the basis of the Bush Administration’s new preemption policy, largely unknown to most Americans, which says that once the FDA approves a drug and its label, citizens may not sue a company for failing to warn about a risk not listed on the label, even in cases like this where the plaintiff can prove that the company knew about the risk and intentionally concealed it.

SSRI’s are antidepressants known as selective serotonin reuptake inhibitors and include Paxil, Eli Lilly’s Prozac, Zoloft by Pfizer and Celexa and Lexapro marketed by Forest Labs. Wyeth’s Effexor, Lilly’s Cymbalta and Glaxo’s Wellbutrin are not considered SSRI’s, but they also carry a warning about an increased risk of suicidality in young people.

Two SSRI suicide cases are now awaiting a joint decision from the Third Circuit Court of Appeals for which oral arguments took place in December 2007.

In the case of Colacicco v Apotex, the US District Court for the Eastern District of Pennsylvania was the first to dismiss a failure-to-warn claim based on the new preemption policy, and in McNellis v Pfizer, the US District Court for the District of New Jersey found no preemption.

Also unbeknownst to most Americans, the Bush Administration is instructing judges to dismiss the lawsuits against the SSRI makers in amicus briefs filed by the government’s top attorneys, who also attend hearings when necessary to argue on behalf of the SSRI makers during oral arguments on motions to dismiss.

In fact, in regard to requiring a warning about suicide, during oral arguments in the Third Circuit, Bush Administration attorney Sharon Swingle told the court that the FDA “had again and again and again made an expert determination that the warning was not appropriate.”

She maintained that the claims were preempted because the SSRI makers were not allowed to add warnings to the label under any circumstances without prior approval from the FDA.

At one point, the court asked an attorney for an SSRI maker, “assume for the moment that you had reasonable evidence of an association between your product and a serious hazard or a serious possibility of an enhanced suicide risk.”

Under federal regulations, “what would be your obligation?”

The attorney stated, “our obligation would be to take that information to the FDA, advise the FDA of the information.”

“It then would be the FDA’s determination whether that represented a substantial relationship,” he told the court.

“So if you had evidence internally that there’s an enhanced risk of suicide, you would go to the FDA,” the court said, and asked, “And how long would that take?”

“I do not know the answer to that, your Honor,” the attorney said, and the court asked, “Could it take months?”

“I imagine it would depend on the seriousness –,” the attorney stated.

“But isn’t there a significant possibility that additional people then might have the same consequence that happened here with McNellis, or with Colacicco and McNellis’s father?” the court asked.

The attorney said, “on the basis of the information that was available we would take it per FDA directive to the FDA and they would make the determination whether the label should be changed.”

“Other people could then,” the court continued, “possibly have an enhanced risk of suicide and other people may commit suicide as a result of taking your product?”

“We would be bound by law to comply with the FDA, then to comply with its directives,” the attorney replied.

“Are they requiring that you go through them first rather than act on your own?” the court asked.

“That’s exactly correct, your Honor, because there is the bigger issue of the –” the attorney stated.

However, at the end of the hearing, Pennsylvania attorney Derek Braslow proved beyond any doubt that the claims made by the Bush Administration attorney and the attorneys for the drug makers were blatant lies, when he informed the court that Glaxo had “independently, strengthened their warning in May 2004 to warn about increased suicidality and worsening depression in everyone, not just children.”

“There was specifically in bold letters a new warning with respect to increased suicidality and worsening depression in May 2004,” he stated.

“Glaxo changed the label on their own without FDA approval,” Mr Braslow told the court.

Glaxo did it again in May 2006, he said, when they sent out a “Dear Healthcare Professional” letter and warned about the increased risk of suicidality and suicidal behaviors with Paxil in persons of all ages.

During oral arguments in the O’Neal case on January 21, 2008, Glaxo’s preemption argument was presented by King & Spalding attorney Mark Brown, who just happens to be a former Associate Chief Counsel for the FDA from the first Bush Administration.

The family intends to ask the court to reconsider the ruling in the O’Neal case, according to a statement by Baum Hedlund.

In his report, Dr Glenmullen sums up the inadequacy of the system, including the FDA, that allowed Glaxo to keep this vital information hidden from prescribing doctors and patients for nearly 2 decades and states, in part:

“One of the most sobering aspects of the story of Paxil-induced suicidality is that GlaxoSmithKline was not forthcoming with its data demonstrating the risk and regulatory agencies like the FDA did not take the initiative to get to the bottom of and expose the true risk.”

“Rather, the impetus came from attorneys and medical experts surprised by what they found in GlaxoSmithKline’s confidential documents, which only came to light through litigation.”

“The GlaxoSmithKline documents that have so-far made it into the public record have in turn been critical to educating patients, the public, and the media about the true risk. The media – particularly the BBC in England – played a crucial role in turning the tide in the history of Paxil-induced suicidality.”

According to Dr Glenmullen, “it was the diligent efforts of plaintiff’s attorneys that forced GlaxoSmithKline to divulge the inaccurate counting method to the FDA.”

Another leading expert on pharmacology, Dr Peter Breggin, warns that an 8-fold increased risk of suicidality in controlled clinical trials could mean 80-fold in actual practice. “We can’t determine exactly how much greater the risk will be in clinical practice but it will be astronomically greater,” he advises.

In actual practice, he explains, many patients are already suicidal when they start taking the drug, increasingly the likelihood that the drug can push them over the edge.

Despite the warnings to watch patients closely, Dr Breggin says, busy doctors do not monitor patients properly. He explains that they are almost never evaluated for suicidality and are often given multiple drugs at the same time, by doctors who know little about their adverse effects on the mind.

Glaxo is facing lawsuits from surviving family members of Paxil suicide victims all over the country and is attempting to use preemption to avoid public trials for good reason. The first case to go before a jury in Wyoming in 2001, involved a man who shot his wife, daughter and infant granddaughter before shooting himself after being on Paxil for just a matter of days.

The trial resulted in a verdict against Glaxo for $6.4 million after the jury weighed the expert testimony of famed pharmacologist Dr David Healy, who presented a summary of Glaxo’s hidden suicide data on Paxil, against the testimony of the industry-funded SSRI defender Dr John Mann, whose name appears on many of the studies issued over the years, some as late as 2007, that steadfastly proclaim that SSRI’s are not linked to suicide and should be prescribed to children.

In addition to Dr Healy’s revelations about hidden data showing that Glaxo was aware of the increased risk, Dr Mann’s credibility was likely weighed against the fact that he had received over $30 million in research funding from drug companies between the early 1990’s and the trial in 2001, which was brought out during his testimony by Houston attorney Andy Vickery.

Mr Vickery also established that, roughly 10 years and $30 million earlier, Dr Mann had published a paper stating that SSRI’s could increase suicidality in a small subset of patients.

In his report, Dr Glenmullen states that, since Glaxo had the original data in 1989 that showed a greater than eightfold increased risk, it should have warned doctors and patients about the risk “a decade-and-a-half ago when Paxil was first approved by the FDA.”

The report includes portions of an April 29, 1991 report, written by Glaxo psychiatrist Dr Geoffrey Dunbar, sent to the FDA in response to a specific request for information on suicidality in which Glaxo openly lies in stating: “analyses of our prospective, clinical trials for depression show that patients who were randomized to Paxil therapy were at no greater risk for suicidal ideation or behavior than were patients randomized to placebo or other active control therapies.”

Dr Glenmullen notes the importance of the date that this false data was submitted because the FDA had scheduled a hearing with a nine-member advisory panel for September 20, 1991, to discuss concerns raised a year earlier about the possibility of Prozac making patients suicidal. Paxil was not approved for use in the US until December 2002.

In his report, Dr Glenmullen points out that 5 of the 9 members on the advisory panel had conflicts of interest with drug makers and that 2 psychiatrists, Dr David Dunner of the University of Washington in Seattle and Dr Stuart Montgomery from England, had done research on Prozac for Eli Lilly, and later played crucial roles in Glaxo’s publishing of what he calls “bad” suicide numbers in the Paxil story.

Dr Glenmullen’s report includes portions of a September 19, 1991, memo distributed to over 20 senior staff the day before the hearing with a “Statement to be used to respond to inquiries re Paxil/Suicide,” which claims explicitly that during GlaxoSmithKline’s studies: “the incidence of suicide was lower among patients receiving Paxil than among those receiving placebo.”

This was the statement the company ordered employees to make, even though 5 patients on Paxil committed suicide while no patients in the placebo group did. In addition, Dr Glenmullen points out that, up to 1989, seriously suicidal patients were excluded from Glaxo’s studies, and therefore “anyone who became seriously suicidal during the studies only became so after being given Paxil or a placebo.”

Yet the actual numbers show that there were 40 suicide attempts in the clinical trials by patients taking Paxil compared to 1 suicide attempt in the placebo groups.

Despite the poor quality of the data available to the advisory committee, and despite the many conflicts of interest of its members, one third of the members still voted for a warning in 1991, Dr Glenmullen points out.

Three months later, in December 1991, Dr Dunner, together with Glaxo psychiatrist Dr Dunbar, presented Glaxo’s Paxil data with the “bad” numbers at a meeting of the American College of Neuropsychopharmacology (ACNP) in Puerto Rico.

During the presentation, the doctors told the ACNP: “Suicide and suicide attempts occurred less frequently with Paxil than with either placebo or active control,” according to the Glenmullen report.

The ACNP’s members are considered prominent academic psychiatrists who specialize in pharmacology, and the group has issued a number of position papers over the years which consistently denied a link between SSRI’s and suicidality.

Dr Mann led an ACNP task force which included Dr Fred Goodwin, Dr Charles O’Brien and Dr Robinson, which supposedly reviewed all the clinical trial data on SSRI’s and issued a consensus statement with the position that SSRI’s did not increase the risk of suicidal behavior, which was published in the journal Neuropsychopharmacology in 1993.

In March 1995, Dr Dunner, Dr Montgomery and Dr Dunbar published the paper, “Reduction of suicidal thoughts with paroxetine in comparison with reference antidepressants and placebo,” in the European journal Neuropsychopharmacology. This paper included a table with the “bad” numbers and claimed that other antidepressants were more likely to increase the risk of suicide than Paxil.

The paper specifically states: “Consistent reduction in suicides, attempted suicides, and suicidal thoughts, and protection against emergent suicidal thoughts suggest that Paxil has advantages in treating the potentially suicidal patients.”

On July 5, 1995, Glaxo’s marketing department issued a memo urging its sales force to use the Dunner-Dunbar paper to reassure doctors who were concerned over Paxil-related suicide that there was no need for concern.

The fact is, documents obtained in litigation prove that the FDA has known about the suicide risks of SSRI’s for roughly 23 years. Two years before Prozac was approved, in May 1985, the FDA’s chief investigator, Dr Richard Kapit, wrote: “Unlike traditional tricyclic antidepressants Fluoxetine’s profile of adverse side effects more closely resembles that of a stimulant drug than one that causes sedation.”

“It is Fluoxetine’s particular profile of adverse side-effects which may perhaps, in the future give rise to the greatest clinical liabilities in the use of this medication to treat depression,” he noted.

Dr Kapit’s review described data from 46 clinical trials with a total of 1,427 patients and under the section, “Catastrophic and Serious Events,” he listed 52 cases of “egregiously abnormal laboratory reports which were the reason for early termination,” and “additional adverse event reports not reported by the company were revealed on microfiche.”

“In most cases,” he wrote, “these adverse events involved the onset of an unreported psychotic episode.”

There were ten reports of psychotic episodes including 2 reports of completed suicides, 13 attempted suicides, 4 seizures, and 4 reports of movement disorders. In 1985, Dr Kapit recommended “labeling warning the physician that such signs and symptoms of depression may be exacerbated by this drug”.

When Prozac was approved, no such warning was issued.

Two weeks after the FDA advisory panel met in February 2004 to review the data on SSRI’s to determine whether they were linked to suicide, Dr Healy sent a report to Peter Pitts, Associate Commissioner for External Relations, at the FDA, in response to an invitation by Dr Robert Temple for a submission of the details of studies referred to in the course of a presentation at the meeting.

“A great number of the patient testimonies in the course of the Feb 2nd hearing were from individuals who became suicidal on an SSRI when their underlying disorder was Lyme Disease, migraine or a condition such as social phobia,” Dr Healy pointed out.

He also noted that this had been the case in the 1991 hearings, when it was framed by FDA’s Dr Temple as follows:

“The discussion we heard earlier showed that people who commit suicide are highly likely to have a diagnosis of depression, which means that somebody identified them as in a high-risk category. But there were still a significant number of people who committed suicide without having that sort of diagnosis and I guess I would like some advice or discussion on who those people were.”

“The anecdotes that one hears that are most evocative to me anyway are not the ones where people who have a 20-year history of suicidal ideation and then finally do it – that is not too surprising – it is where they assert that there has never been anything in their minds like that before and yet now they have suddenly become excessively concerned with suicide and may even do it.”

Dr Healy’s analysis submitted to the FDA included the data from the pediatric trials on suicidality and hostility, including some that were concealed for years. To distinguish the difference between suicide caused by SSRI’s verses suicide caused by the underlying depression, he separated the data on children who were treated for depression and children who were treated for obsessive compulsive disorder or social phobia.

The analysis found that SSRI’s can cause some children who are not depressed to become suicidal when taking the drugs for other conditions. From a pool of 931 depressed patients taking SSRI’s versus 811 depressed patients taking placebo, Dr Healy determined that there were 52 suicidal acts by patients on SSRI’s versus 18 in the placebo group.

In a pool of 638 patients taking SSRI’s for other disorders versus 562 patients taking a placebo, there were 10 suicidal acts in the SSRI group versus 1 in the placebo group.

When these data sets were combined, there were 62 episodes of suicidality in the 1,569 patients on SSRI’s versus only 19 episodes in the 1,373 patients on a placebo.

In his submission to the FDA, Dr Healy also explained that he had conducted his own trial on Zoloft in 2000 with 20 “healthy volunteers,” meaning they had no mental disorder when entering the trial, and two of the Zoloft patients became suicidal. This type of study provides the strongest evidence of drug-induced suicidality because it’s impossible for drug companies to claim that a patient became suicidal as a result of the underlying depression.

Seven years ago, during the Wyoming jury trial involving the tragic Paxil-induced murder-suicide, the man’s physician testified that he may not have prescribed Paxil if a warning regarding homicide and suicide had been added to the drug’s label.

In his report released last month, Dr Glenmullen offers the following heart-wrenching conclusion to the court: “It is my opinion to a reasonable degree of medical probability that if GlaxoSmithKline had provided a warning all these years, Benjamin Bratt would still be alive today.”

On April 24, 2004, the Lancet medical journal published an editorial entitled, “Depressing Research,” with the following comments that surely ring doubly true today for the Bratt family, as well as all the other families whose children committed suicide while on SSRI’s:

“It is hard to imagine the anguish experienced by the parents, relatives, and friends of a child who has taken his or her own life. That such an event could be precipitated by a supposedly beneficial drug is a catastrophe. The idea of that drug’s use being based on the selective reporting of favourable research should be unimaginable.”

Filed under: 2008, Baum, Braslow, Breggin, Colacicco, FDA, FDA hearing, Fraud, ghostwritten, Glaxo, KOL, Mann, Paxil, Preemption, SSRIs, Study 329, suicide, Vickery

Lawmakers Catch Glaxo Hiding Paxil Suicide Risks – Again (Part II)

Evelyn Pringle February 13, 2008

Apparently, GlaxoSmithKline is still trying to hide damaging information about Paxil, because 9 pages of a report released from under a court order last month, are not available to the public. However, Senator Charles Grassley has instructed Glaxo to provide him with the full report by February 14, 2008.

In the report, which is dated roughly 6 months ago on June 29, 2007, Harvard Professor, Dr Joseph Glenmullen reveals that Glaxo had clinical trial data since 1989 which showed that Paxil increases the risk of suicide by more than 8-fold compared to patients who received a placebo.

The report was submitted in O’Neal v Glaxo, a lawsuit filed in a California federal court by the surviving family members of Benjamin Bratt who committed suicide at age 13 while on Paxil. The family is represented by the California law firm of Baum, Hedlund, Aristei & Goldman.

On January 30, 2008, the judge dismissed the case on the basis of the new preemption policy of the Bush Administration, but the family intends to ask the court to reconsider the ruling, according to Baum Hedlund.

In his report, Dr Glenmullen also makes a plea for public disclosure of all information that remains sealed under court orders on the basis of Glaxo’s claim that the documents contain trade secrets and states:

“Given the importance of GlaxoSmithKline’s internal documents, it is unfortunate that so many of the documents cited in this report and the attached Appendix are still confidential.”

“Given the stakes for public health and safety, GlaxoSmithKline should not be permitted to claim the documents are proprietary trade secrets.”

“All the documents should be made part of the public record so the full story of Paxil-induced suicidality can be told and the additional necessary steps can be taken to fully protect patients and the public.”

Dr Glenmullen also mentions a companion report related to children and adolescents and a “Specific Causation Report” in the case of Benjamin Bratt, and Senator Grassley has instructed Glaxo to provide him with a copy of that report as well.

In what can only be viewed as an eerily prophetic comment, in a letter back on September 16, 2004, to the Secretary of Health and Human Services, and the acting FDA Commissioner at the time, Senator Grassley warned: “I intend to keep the FDA’s feet to the fire to insure that the American public is knowledgeable about the risks of SSRI’s.”

SSRI’s refer to antidepressants known as selective serotonin reuptake inhibitors that include Paxil, Eli Lilly’s Prozac, Zoloft by Pfizer and Celexa and Lexapro marketed by Forest Labs, along with their generic counterparts. Lilly’s Cymbalta, Wyeth’s Effexor and Glaxo’s Wellbutrin are often referred to as SSRI’s but they are slightly different chemically. However, the new antidepressants all carry the same warnings about the suicide risks.

Senator Grassley’s letter followed the vote by an FDA advisory committee for a black box warning about the increased risk of suicide with kids to be added to the drugs’ labels.

His angry tone, and not so subtle threat, was due to the fact that, during the advisory committee meeting, it became apparent that not only Glaxo, but all the SSRI makers, had concealed and misrepresented clinical trial data for years in the published medical literature which clearly indicated that there was an increased risk of suicidality with SSRI use.

In fact, as soon as Glaxo’s was asked about the hidden studies by regulators in the UK, Glaxo issued a “Dear Doctor” letter to physicians in England saying Paxil should not be prescribed to children because it “failed” to work any better than a placebo and frequently caused “hostility, agitation, emotional lability (including crying, mood fluctuations, self-harm, suicidal thoughts, and attempted suicides.)”

Glaxo did not issue any such warning to doctors in the US.

The paper that garnered the most wrath from pharmacology experts all over the world was published in the July 2001 issue of the Journal of the American Academy of Child and Adolescent Psychiatry on Paxil study 329, which was conducted from 1993 through to late 1995 or early 1996, according to a leading pharmacology expert, Dr David Healy.

Twenty academics, considered to be the tops in their field, signed off on the study. The main authors of paper on the study were later found to be in constant contact with Glaxo when the media began reporting that the data published was fraudulent, and include Dr Martin Keller, Dr Neil Ryan and Dr Karen Wagner.

In the paper, the authors write: “Of the 11 patients only headache (one patient) was considered to be related to the treatment,” and Paxil is “generally well tolerated and effective.”

However, when the actual study was analyzed in 2003, it showed suicidal acts by 5 out of 93 children on Paxil compared to no suicidal acts in the 89 children who received placebo.

On January 29, 2007, the BBC’s Panorama broadcast, “Secrets of the Drug Trials.” Attorney Karen Barth Menzies obtained many of the secret Paxil documents that were quoted during litigation, and she explained how Glaxo found ways “to blow up out of proportion the supposed benefits in Study 329 and downplayed the negative findings.”

Glaxo recruited the opinion leaders to put their names on the published 329 study, she said, because they were academics whom everybody looked up to, and the company knew that doctors would be far more likely to prescribe Paxil after listening to these doctors than they would be if approached by Glaxo salespersons.

One letter that was quoted, revealed that these so-called opinion leaders never even wrote a paper. The letter was from a ghost writer to Dr Keller, informing him that all the necessary materials were enclosed for him to submit the study to a journal for publication. The packet even included a cover letter, with instructions telling Dr Keller to: “please re-type on your letterhead. Revise if you wish.”

Dr Wagner, along with Dr Graham Emslie, was also responsible for publishing papers on studies that resulted in Prozac’s approval for children, and Dr Wagner and Dr Keller were also investigators on Zoloft studies and several of the unpublished Paxil studies.

In the October 4, 1999 Boston Globe, Alison Bass reported that in 1998, as a professor at Brown University, Dr Keller was forced to forfeit “hundreds of thousands of dollars” in state grant money and was paid more than $500,000 in consulting fees in 1998, most of it from companies whose drugs he touted in medical journals and at conferences.

In the report, Ms Bass pointed out that Keller was a valuable resource for the University, and had brought in about $14.4 million in research funding from drug companies and federal agencies since 1993.

According to the report, in 1998, the year Keller published 3 studies with colleagues in the Journal of the American Medical Association and the Journal of Clinical Psychiatry touting the efficacy of Zoloft, he received $218,000 in personal income and more than $3 million in research funding from Zoloft maker Pfizer.

Several ethicists contacted by the Globe said Keller’s unusually large consulting fees, a total of $556,000 in 1998 and $444,000 in 1997, constitute the most serious potential conflict they’ve heard of yet, Ms Bass noted.

Dr Wagner received an onslaught of criticism from experts all over the world when she misrepresented trial data in a paper on Zoloft, claiming it was safe and effective for use with children. On November 29, 2004, Barry Meier wrote, “Contracts Keep Drug Research Out of Reach,” in the New York Times, and reported that over the past decade, Dr Wagner from the University of Texas Medical Center in Galveston had led or worked on some 20 studies published in medical journals and had also “attracted a large number of industry-financed studies, including those aimed at testing whether antidepressants approved for use in adults were safe and effective in children and adolescents.”

In a financial filing with the university in December 1999, Mr Meier found the same month that a Zoloft trial began recruiting patients, Dr Wagner disclosed that she had received more than $10,000 from Pfizer but she did not provide details.

She also did not respond to written questions about the payments but a lawyer for the school, told Mr Meier that Dr Wagner had told him that Pfizer had paid her $20,500 during the course of the Zoloft trial.

Mr Meier also noted that academic researchers routinely receive speaking and consulting fees from companies whose products they test and at Galveston the financial threshold for such a review is $10,000. But the school lawyer, told Mr Meier that the center had been unable to locate records related to Pfizer’s payments to Dr Wagner.

Glaxo’s study 329 was successfully used to promote Paxil for children, and sales to kids skyrocketed to $55 million in 2002 alone. It also served as the smoking gun in a lawsuit filed against Glaxo by New York Attorney Elliot Spitzer, charging Glaxo with fraud for promoting the off-label use of Paxil to children while concealing and misrepresenting the data from 5 studies that showed the increased suicide risks and the fact that Paxil did not work with children. Glaxo settled out of court to shut that lawsuit down within 2 months.

In 2003, after reviewing the same fraudulent studies, the UK banned the use of Paxil with children, and the FDA scheduled an advisory committee meeting in February 2004 to review the data on all SSRI’s.

In response to the announcements by the regulatory agencies, the American College of Neuropsychopharmacology (ACNP), which designated a Task Force in the early 1990’s to review the SSRI trial data, and subsequently published an position paper saying SSRI’s were not linked to suicide, appointed a new Task Force in September 2003, to study the matter again.

This Task Force was made up of many of the same authors whose published papers were under attack for being fraudulent and included Dr John Mann, Dr Graham Emslie, Dr Karen Wagner, Dr Neal Ryan, Dr Andrew Leon, Dr Fredrick Goodwin, Dr David Shaffer, Dr Beardslee, Dr Jan Fawcett, Dr Herbert Meltzer and Dr Ross Baldessarini.

Two weeks before the advisory committee meeting, the Task Force issued a report, once again claiming SSRI’s did not cause suicide, and began making what many experts condemned as preemptive statements in the media to influence the advisory committee to vote against adding a warning about the risk of suicide to SSRI labels.

On January 21, 2007, WebMd’s headline on the internet stated: “Group Finds No Suicide-Antidepressant Link”.

“Our conclusion is that when you look at the SSRI’s as a group, there is evidence they are effective for treating depression in children and adolescents,” Dr Mann told WebMD.

“Instead of being a risk for suicidal behavior, they are potentially therapeutic,” he stated.

In fact, the $30-million Dr Mann, who admitted under oath in a jury trial that it was possible that he got over $30 million in research funding from drug companies over a 10-year period, said the group found strong evidence that SSRI’s help depressed kids and that suicide rates started going down when SSRI’s became available.

He claimed that a 14-year study showed a decline in suicide rates in kids. “Across 15 countries there has been a 33% decline in suicide rates amongst youths,” he told WebMD.

“Doctors must go on treating depression, and SSRI’s appear to be a reasonable choice,” he stated.

The FDA even allowed Task Force members Dr Andrew Leon and Dr Neil Ryan to participate as voting members of the February 2, 2004 advisory panel.

The day after a September 2004 advisory committee finally voted to add a black box warning to the SSRI labels, on September 14, 2004, Senator Grassley issued a press release stating that the FDA “needs to learn an important lesson from what’s developed this year on the matter of kids and antidepressants.”

“Transparency in government is the best policy,” he noted. “Parents and doctors should not be left in the dark, and especially when information that’s available could be a matter of life and death.”

“Given the scientific findings,” he added, “it’s obvious that the strongest label warning for this class of drugs is critically important for the health and safety of young Americans.”

“These measures are especially critical,” he said, “since I also understand from previously released studies and from the Advisory Committee’s own deliberations that only one of the nine antidepressant drugs has been proven to provide any benefit to children and adolescents.”

“In fact,” he pointed out, “in almost all cases, the FDA’s own data demonstrates that these drugs actually perform no better than do placebos.”

In a September 16, 2004, letter, Senator Grassley asked the FDA to “very quickly and fully consider” the recommendations for the black box and med guides, “before the lives of more children are needlessly lost because parents and others lack adequate, readily understandable information when they most need it.”

He also brought up the issue of informed consent and said he was curious about the FDA’s rationale for not requiring doctors to provide a clear, informed consent document that parents must read, understand and sign before accepting a prescription, as the FDA had done with the drug Lotronex, due to a 1 in 300 risk of ischemic colitis in patients.

In the case of antidepressants, Senator Grassley pointed out, “a suicide-related event involving Prozac (fluoxetine) is about 1 in 15 according to the TADS study, and about 1 in 30 for all SSRI’s, according to FDA’s own study.”

The letter said that the informed consent form should at least include the following points: (1) Only Prozac has been shown to be effective in treating depression in children and adolescents, and is the only drug approved for this; (2) All others have been shown to be no different than a placebo, and their use in the treatment of children and adolescents is not an approved use; (3) All antidepressants increase the risk of suicidality, and (4) The risk of a suicide event (planned or actually attempted) is one for every 15 to 30 children and adolescents taking the antidepressant.

Senator Grassley also asked what the FDA planned to do about educating doctors and the public about the risk-benefits of antidepressants, especially in children. Obviously, the short answer to that question more than three years later is, not a thing.

In fact, in the January 17, 2008, Wall Street Journal, David Armstrong and Keith Winstein reported that, “the effectiveness of a dozen popular antidepressants has been exaggerated by selective publication of favorable results, according to a review of unpublished data submitted to the Food and Drug Administration.”

“As a result,” they wrote, “doctors and patients are getting a distorted view of how well blockbuster antidepressants like Wyeth’s Effexor and Pfizer Inc.’s Zoloft really work,” in discussing research led by Erick Turner, a psychiatrist at Oregon Health & Science University, published in a study in New England Journal of Medicine.

They also point out that sales of antidepressants total about $21 billion a year.

In all the studies, old and new, which promote the off-label sale of SSRI’s for children with claims that the drugs work and do not cause suicide, almost without fail, the same names appear as investigators and authors. A complete listing includes Dr John Mann, Dr Martin Keller, Dr Graham Emslie, Dr Frederick Goodwin, Dr Karen Wagner, Dr Neal Ryan, Dr Charles Nemeroff, Dr David Dunner, Dr Andrew Leon, Dr John March, Dr David Shaffer, Dr John Rush, Dr Mark Olfson and Dr Robert Gibbons.

This time around, in addition to going after Glaxo for concealing and misrepresenting the data that showed an 8-fold increased risk of suicide, somebody needs to take the bull by the horns and see to it that these industry-funded quacks get thrown in the slammer.

It’s also more than apparent that a few FDA officials belong there as well.

Filed under: 2008, Fraud, ghostwritten, Glaxo, KOL, Mann, Paxil, SSRIs, Study 329, suicide

Cancer Industry Fights To Keep Obscene Profits – Part I

Evelyn Pringle January 2008

The cancer industry derives most of its profits from chemotherapy. Both the drug companies and the treatment providers profit from the chemotherapy drugs and the medications used to combat the side effects. The obscene profits made off chemotherapy override any incentive to find a cure or better treatments.

Doctors administer chemotherapy in their offices, buy the drugs at a lower cost than what insurance companies and public health care programs pay and pocket the difference.
This system provides an incentive to overuse chemotherapy and the most expensive medications.

A 2001 study by the National Institute of Health found that about a third of Medicare beneficiaries received chemotherapy in the last six months of their lives, even through their cancer was unresponsive to chemotherapy, which “strongly suggests overuse of chemotherapy at the end of life,” the report said.

A 2006 study in the Health Affairs journal entitled, “Does Reimbursement Influence Chemotherapy Treatment for Cancer Patients,” determined that reimbursement had a direct effect on which drugs doctors prescribed for cancer patients. For instance, the study found that a $1 increase in reimbursement resulted in the use of chemotherapy drugs that cost $23 more.

A survey by Dr Neil Love, entitled, “Patterns of Care,” found that for first-line chemotherapy of metastatic breast cancer, 84-88% of the academic center oncologists who did not derive profits from infusion chemotherapy prescribed an oral drug, only 13% prescribed infusion drugs and none prescribed the expensive, highly-remunerative drug docetaxel.

In contrast, community-based oncologists who did profit from infusion chemotherapy, prescribed an oral dose of a drug only 18% of the time. Seventy-five percent of these oncologists prescribed infusion drugs and 29% prescribed the expensive, highly-remunerative drug docetaxel.

On October 1, 2006, Alex Berenson reported in the New York Time that worldwide spending on cancer drugs was $24 billion in 2004 and was expected to rise to $55 billion in 2009, “making oncology treatments the biggest drug category,” citing data provided by IMS Health.

In 2005, the government reduced Medicare reimbursement rates for cancer drugs and medications used to counter the side effects of chemotherapy administered in doctors’ offices and cited reports that showed oncologists made $700 million in 2002 from Medicare profits.

“Marketing the Spread” occurs when a drug maker uses the difference between the price paid for a drug by public health care programs like Medicaid and Medicare and the actual cost of the drug charged to doctors or pharmacists as a tool for selling products.

A September 2001 report by the Government Accountability Office cites the list price for one drug used to treat some types of colon cancer at $18.44, with Medicare paying 95% of that cost, while oncologists could purchase it for $2.77.

The GAO also reported that the 86% spread for the cancer drug leucovorin calcium meant that, “Medicare beneficiary’s co-pay alone was actually more than the physician or supplier paid for the drug.”

Before 2005, Medicare paid a markup of 20% to 100% on many injectable drugs, and doctors kept the difference as profit, after certain expenses. The amounts that doctors billed Medicare for injectable drugs rose from $2.9 billion in 1997 to $10.9 billion in 2004.

The Times report shows that doctors were made aware of the amount of money that could be made. Citing documents from a lawsuit filed against Schering-Plough, Johnson & Johnson, AstraZeneca and Bristol-Myers, Mr Berenson reported that the drug companies sometimes “calculated to the penny” how much profit doctors could make and that “sales representatives shared those profit estimates with doctors and their staffs.”

As an example, he quotes a document from 1998 in which Schering-Plough told sales representatives that using the drug Intron-A, for the treatment of bladder cancer, could produce a profit per patient of “$2,373.84 for our physicians just on the drug alone.”

On August 29, 2006, the US attorney for the District of Massachusetts announced that the Schering-Plough Sales Corporation, a subsidiary of Schering-Plough, would pay $435 million to settle criminal and civil allegations relating in part to off-label marketing of drugs, including the oncology drugs, Temodar and Intron A.

Intron A was FDA approved for conditions including chronic hepatitis B, chronic hepatitis C and malignant melanoma. and allegations were made that the Sales Corporation promoted Intron A for treatment of superficial bladder cancer.

Temodar was approved for three specific types of brain cancers, and the Sales Corporation was alleged to have promoted Temodar for treating other types of brain tumors and metastases.

According to the government, pre-tax profits that resulted from the off-label marketing of Temodar and Intron A amounted to $124.2 million. The Sales Corporation agreed to pay a criminal fine of $180 million and was permanently excluded from participation in Medicaid, Medicare and other federal health care programs.

Schering-Plough settled the civil liabilities for losses to public health care programs for a total of $255 million.

In June 2003, AstraZeneca paid $355 million to settle allegations that it marketed the spread and concealed the best price for the prostate cancer drug Zoladex. AstraZeneca pleaded guilty to conspiring to violate the Prescription Drug Marketing Act by supplying free samples of Zoladex to physicians, knowing they would bill Medicare and Medicare beneficiaries a 20% co-pay for the drug.

As part of the plea deal, AstraZeneca agreed to pay a criminal fine of $63.9 million, more than $279 million to settle False Claim liabilities to the US and $11.2 million to the states.

In October 2001, TAP Pharmaceuticals, a joint venture between Abbott Laboratories and Takeda Chemical Industries, paid $875 million to settle charges that it marketed the spread and concealed the best price for the prostate cancer drug Lupron.

TAP pleaded guilty to conspiring to violate the Prescription Drug Marketing Act by giving free samples of Lupron to doctors and allowing them to bill Medicare and Medicare beneficiaries a 20% co-pay for the drug.

TAP paid a $290 million fine to settle the criminal charges, paid the federal government $559.5 million to settle civil liabilities under the FCA and $25.5 million to the 50 states and the District of Columbia to settle the Medicaid fraud liabilities.

On September 20, 2005, the Justice Department announced that GlaxoSmithKline would pay over $150 million to resolve allegations that the company violated the False Claims Act through fraudulent drug pricing and marketing of two anti-emetic drugs, Zofran and Kytril, used primarily in conjunction with oncology and radiation treatment to control nausea and vomiting.

The government also alleged that Glaxo engaged in a “double-dipping” billing scheme by encouraging customers to pool leftover vials of Kytril to create an extra dose, which would then be administered to a patient and re-billed to Medicare and other federal healthcare programs.

Of the $150 million settlement, the federal recovery is approximately $140 million and the states’ recovery for their share of Medicaid is $10 million.

“The Justice Department will continue to pursue these types of fraud schemes vigorously to make clear that we will not tolerate fraudulent pricing practices designed to reap profits for drug companies and doctors at the expense of healthcare programs for the poor and the elderly,” said Assistant Attorney General Peter Keisler of the Justice Department’s Civil Division in the press release.

“As our nation struggles to contain healthcare costs, we must ensure that drug manufacturers do not take advantage of the poor, the elderly or the sick by illegally inflating the price of prescription drugs. That a manufacturer would fraudulently inflate the cost of a drug used primarily to reduce the side effects of cancer treatments is unconscionable,” said US Attorney R Alexander Acosta.

In August 2006, Glaxo paid another $70 million to settle a class action brought on behalf of Medicare beneficiaries who paid some or all of the costs of Zofran and Kytril, along with private insurers and union benefit funds which pay for drugs on behalf of their members, and state Medicaid programs which paid cost-sharing amounts for Medicare beneficiaries.

The 2007 third quarter SEC report filed on November 9, 2007, by Amgen, the maker of Aranesp and Epogen, Erythropoiesis Stimulating Agents, or ESA’s, drugs that were FDA approved to treat anemia caused by chemotherapy and in patients undergoing kidney dialysis, shows that the company is facing massive litigation and government investigations over charges that the company engaged in illegal marketing and promotion in the sale of the ESA’s for uses that were not approved that have now been shown to cause death and serious injuries in patients.

On August 8, 2007, Ironworkers v Amgen, on August 15, 2007, Watters (State of Michigan) v Amgen and on August 28, 2007, Sheet Metal v Amgen, third-party-payor class action lawsuits were filed in the Central District of California.

According to the SEC filing, similar to previously filed third-party-payor class actions, in each action, the plaintiff alleges that Amgen marketed its anemia medicines for “off-label” uses, or uses that are not approved by the FDA, and as a result, the plaintiffs paid for unwarranted prescriptions.

Specifically, the complaints allege that Amgen promoted the drugs for: treating cancer patients who are not on chemotherapy; treating quality of life symptoms associated with anemia, such as fatigue, and reaching Hb targets above the FDA-approved level.

Each plaintiff asserts claims under California’s consumer protection statutes and for breach of implied warranty and unjust enrichment, and plaintiffs seek to represent a nationwide class of individuals and entities.

In Sheet Metal v Amgen, the plaintiff also name privately-owned dialysis centers DaVita and Fresenius as co-defendants and includes a RICO claim. These two dialysis chains reportedly each account for about a third of the market

The SEC filing also notes that two previously disclosed state derivate lawsuits, Larson v Sharer and Anderson v Sharer, were consolidated into one action captioned Larson v. Sharer et al before the Ventura County Superior Court and that a third state derivate lawsuit, Weil v Sharer, was filed on August 13, 2007, in Ventura County Superior Court and was also consolidated with the Larson action.

On August 20, 2007, the class action Harris v Amgen was filed against Amgen and certain of its Board of Directors in the California Central District Court, with claims that the defendants breached their fiduciary duties by failing to inform current and former employees who participated in the Amgen Retirement and Savings Manufacturing Plan and the Amgen Savings Plan of the alleged off-label promotion of both Aranesp and Epogen, “while a number of studies allegedly demonstrated safety concerns in patients using ESA’s.”

On November 2, 2007, the Sheet Metal Workers National Health Fund filed suit in the US District Court for the District of New Jersey against Amgen alleging both federal and state antitrust violations, as well as violations of California’s Unfair Competition Law.

The complaint alleges that Amgen engaged in an “anti-competitive tying arrangement and pricing scheme” involving the sale of three products, Neupogen, Neulasta and Aranesp, and seeks injunctive and compensatory relief for this alleged anticompetitive behavior.

According to the lawsuit, Amgen requires oncology clinics to buy Aranesp, a red blood cell stimulant, if they want better prices for the company’s two white blood cell stimulants, Neulasta and Neupogen, which are both used to combat the side effects of chemotherapy.

The two drugs hold 98% of the market in sales to oncology clinics, Maria Vogel-Short reported in the November 9, 2007, New Jersey Law Journal.

The Sheet Metal Workers Fund is a third-party payer of the costs of Aranesp and the putative class is identified as including anyone who paid all or a portion of the cost for Aranesp at an oncology clinic since April 2004.

The plaintiffs’ attorney, David Cohen, of Saltz Mongeluzzi Barrett & Bendesky in Philadelphia and Voorhees in New Jersey, told Ms Vogel-Short that due to Amgen’s pricing arrangement, clinics are forced to pay higher prices for Aranesp. According to Mr Cohen, Procrit costs $80 to $100 per dose, and Aranesp costs $100 to $300.

The SEC filing also notes that securities class actions, Mendall v Amgen, Jaffe v Amgen, Eldon v Amgen, Rosenfield v Amgen and Public Employees’ Retirement Association of Colorado v Amgen, were consolidated into one action captioned, Connecticut Retirement Plans & Trust Funds v Amgen Inc et al before the US District Court for the Central District of California and that the amended complaint was filed on October 2, 2007.

The filing also lists three third-party-payor class actions including the United Food & Commercial Workers Central Pennsylvania and Regional Health & Welfare Fund v Amgen, the Vista Healthplan Inc v Amgen and the Painters District Council No. 30 Health & Welfare Fund v Amgen, pending in the California Central District Court.

According to the SEC report, Amgen has received a subpoena from the United States Attorney’s Office, Eastern District of New York, for production of documents relating to its products on October 25, 2007, and on November 1, 2007, the company received a subpoena from the United States Attorney’s Office, Western District of Washington, for production of documents relating to its products.

Amgen has also received letters from both the House Subcommittee on Oversight and Investigation, Committee on Energy and Commerce and the United States Senate Committee on Finance, with inquiries related to Amgen’s ESA studies, promotions of ESA and the company’s pharmacovigilance program.

Although Amgen manufactures Epoetin, the company granted a license to a subsidiary of Johnson & Johnson to sell the drug in the US under the trade name Procrit, for treatment of cancer patients but not dialysis patients.

J&J is also facing several class-action lawsuits filed by shareholders, and the company has received a subpoena from New York’s attorney general requesting information on the sales and promotional activities related to Procrit.

A May 10, 2007, article in the Wall Street Journal entitled, “Suit Details How J&J Pushed Sales of Procrit,” by Heather Wontesoriero and Avery Johnson, discusses a lawsuit filed against J&J by Dean McClellan and Mark Duxbury, two former Procrit salesmen turned whistleblowers.

The article sites documents on the marketing of Procrit which show that in 2004, after Amgen’s competing drug Aranesp, billed as a longer acting version of Epoetin, was approved, J&J made offers that would allow buyers of Procrit to receive discounts off an already-reduced price, as well as rebates.

For example, one company memo calculates that a physician who bought nearly $1 million of Procrit over 15 months would get a check for $237,885 back, or 24%.

Another program offered hospitals discounts on purchases from across J&J’s product line “– including some huge-selling drugs and medical devices sold by different subsidiaries — if the hospital used Procrit at least 75% of the time when prescribing anti-anemia drugs.”

Mr McClellan also told the Journal that J&J pushed doctors to administer a higher dose of Procrit for cancer patients beginning in the mid-90’s, many years before a higher dose was approved by the FDA.

Initially, he said in the interview, “doctors weren’t buying into it,” in some cases because doctors were worried that Medicare would not reimburse for the cost of an unapproved dose.

Mr McClellan says he was then told to pitch the regimen as more convenient for patients,to pass out free samples, and that at one time he was given roughly 600 cards for free “trial” samples, worth $720,000 in Procrit, to persuade doctors to try the higher dose.

When an Arizona Cancer Center ran into resistance from Medicare over reimbursing $1 million for the unapproved dose, Mr McClellan told the Journal that a company official drafted a letter, under the name of the center director, to Medicare arguing that the dose was appropriate, and he delivered the letter to the Center for the director to sign.

In 2004, the Center announced that J&J’s Ortho Biotech unit had donated $40,000 to the Center to “provide salary support” for a Hematology/Oncology fellow in a newsletter, the Journal reports.

The article points out that Mr McClellan’s allegations are similar to some of those in other lawsuits and investigations into pricing and marketing practices of top-selling products at other J&J subsidiaries and lists Risperdal, an antipsychotic, Topamax, an anti-seizure drug, and the heart medication Natrecor.

The Journal also notes that in June 2006, the Justice Department issued a subpoena to J&J asking for documents on the marketing of orthopedic devices, the US attorney for the District of New Jersey is leading a probe into kickbacks paid to doctors who use implants sold by J&J subsidiary DePuy Orthopedics, and a congressional committee is looking into marketing practices involving the sale of stents by the Cordis subsidiary.

In November 2007, federal Judge Patti Saris, of the United States District Court in Boston, ordered AstraZeneca to pay double damages totaling $12.9 million and Bristol-Myers Squibb to pay $696,000 for overcharging on cancer drugs, in what legal analysts are calling a test case for a nationwide class action seeking hundreds of millions of dollars from Amgen, Abbot Labs and ten other drug companies.

“I conclude,” she wrote in the order, “that defendants’ conduct was both knowing and willful because they knew that Medicare beneficiaries, and thus their insurers, were locked by statute into paying 20 percent of grossly inflated AWP’s, which bore no relation to any average of wholesale prices in the marketplace.”

Judge Patti Saris found AstraZeneca, Bristol-Myers and Schering-Plough liable for damages in June 2007 for selling drugs to doctors at discounts below the published average wholesale prices and encouraging doctors to bill the government and private insurers full price.

In a June 21, 2007, opinion, Judge Saris wrote: “The Medicare statute itself created a perverse incentive by pegging the nationwide reimbursement for billions of drug transactions a year to a price reported by the pharmaceutical industry, thus putting the proverbial pharmaceutical fox in charge of the reimbursement chicken coop. The different pharmaceutical companies unfairly took advantage of the system by setting sky-high prices with no relation to the marketplace.”

The judge said that AstraZeneca acted “unfairly and deceptively” by causing the publication of false and inflated average wholesale prices for the prostate cancer drug Zoladex, which exceeded doctors’ costs by as much as 169%.

Bristol-Myers caused the publication of false and inflated average wholesale prices for five drugs, including Vepesid, Cytoxan, Blenoxane, Rubex and Taxol, which had spreads as high as 500%, and Schering-Plough inflated average wholesale prices for its generic asthma drug albuterol sulfate in a range of 100% to 800%, Judge Saris said.

A most despicable example of how far the chemotherapy industry will go to protect profits, involves an elaborate plot to stop a new class of immunotherapies from entering the market. These new products stimulate the body’s own immune system to attack only cancer cells.

The profiteering chemo gang’s fear of immunotherapies is not without cause. “One day current treatment approaches such as surgery, radiation and chemotherapy, which often kill most but not all of a cancer, could be made obsolete by a potent immune response that eradicates the cancer cells and provides subsequent protection against return and relapse,” according to former FDA official, Dr Mark Thornton in commentary in the May 14, 2007 Wall Street Journal.

Dendreon was the first company to seek approval for a vaccine called Provenge, for the treatment of men in the final stages of prostate cancer whose only other treatment option is chemotherapy with the drug Taxotere, manufactured by Sanofi-Aventis. In clinical trials, the vaccine was shown to extend the lives of men with prostate cancer for nearly twice as long as chemotherapy.

This particularly egregious act of placing profits over the lives of dying cancer patients has resulted in a lawsuit being filed by outraged members of the prostate cancer community against officials within the Bush Administration who orchestrated a plot to block FDA approval of the vaccine, after an FDA advisory panel voted overwhelmingly to recommend approval.

The main industry insiders listed in this plot include FDA Commissioner Andrew von Eschenbach, the director of the FDA’s Office of Oncology Drug Products, Dr Richard Pazdur, along with Dr Howard Scher from the Memorial Sloan-Kettering Cancer Center, and Dr Maha Hussain from Michigan University.

These four people have made millions of dollars off the chemotherapy industry over the past 2 decades and they will undoubtedly make many more millions once their “public service” ends when the Bush administration finally leaves Washington next year, providing that chemotherapy is not replaced with immunotherapies that is.

The conflicts of interest of these doctors could not be more obvious. The top recipients of public and private cancer research funding in the US include Dr Pazdur’s previous employer of 11 years, the MD Anderson Cancer Center at the University of Texas, Dr Scher’s current employer, the Memorial Sloan-Kettering Cancer Center, and Dr Hussain’s Cancer Center at the University of Michigan.

Prior to his appointment to head the National Cancer Institute in 2001, Dr von Eschenbach, was the executive vice president, chief academic officer and the director of prostate cancer research at the MD Anderson Cancer Center.

A huge number of current clinical trials for late stage prostate cancer patients are lead by Dr Scher and Dr Hussain and involve chemotherapy. Many terminally ill men do not want to risk spending their last days on earth experiencing the debilitating side effects of chemotherapy and if Provenge had been approved finding patients to participate in their clinical trials would have been next to impossible.

Because as noted above by Dr Thornton, these new immunotherapies could potentially end the need for chemotherapy, their approval would also mean the end to the obscene profits made from all the drugs administered to combat the side effects of chemotherapy because the new therapies have no serious side effects.

On the same day that the FDA announced the non-approval of Provenge, the agency also denied the approval of Junovan, to treat children and young adults with non-metastatic osteosarcoma, a rare and often fatal bone tumor. The current treatment is tumor resection with combination chemotherapy before and after surgery. There has not been a new treatment option for this disease in more than 20 years

Junovan stimulates the immune system to kill tumor cells and the clinical trial data showed a significantly increased disease-free survival rate. The probability of surviving without a relapse at 6 years, was 66% for patients who received the drug compared to 57% for patients who did not receive the drug.

According to Dr Thornton, “the FDA succeeded in killing not one but two safe, promising therapies designed and developed to act by stimulating a patient’s immune system against cancer.”

“The FDA’s hubris,” he wrote, “will affect the lives and possibly the life spans of cancer patients from nearly every demographic, from elderly men with prostate cancer to young children with the rarest of bone cancers.”

He also noted that the Junovan advisory panel meeting “was chaired by the very physician who launched the PR campaign against Provenge.”

The clinical trials on Provenge were conducted on patients in the last stage of the cancer whose immune systems had already been damaged by radiation and chemotherapy and experts predict that the drugs will work much better with patients in the earlier stages of the disease with healthier immune systems.

The effi�cacy of the vaccine was shown in men who had already failed all conventional therapies. “These advanced stages of cancer are dif�ficult to treat, because the cancer cells have already developed sur�vival mechanisms that make them extremely difficult to eradicate,” according to Dr William Faloon in the article “FDA Rejects Promising Prostate Cancer Drug,” in a special 2007 edition of Life Extension magazine.

“The fact that Provenge� demonstrated such impressive survival benefits in men with these advanced forms of prostate cancer,” he writes, “hints that it could be even more effective if administered in earlier stages of the disease—perhaps at the first sign of metas�tasis or in those men with highly adverse risk factors associated with short survival times.”

Thomas Farrington, president of the Prostate Health Education Network, testified at the FDA advisory committee hearing in March 2007 and recently wrote an editorial on the web site of the Network and stated in part: “I along with all the other survivors and advocates who presented, urged this committee to recommend approval based upon treatment needs and the scientific data from the Provenge clinical trials.”

“We were elated,” he wrote, “when the committee voted 17 to 0 that Provenge was safe and 13 to 4 that it met the FDA’s efficacy standards – an overwhelming recommendation to the FDA for approval.”

“Finally,” he said, “we thought, there would be a treatment for terminally-ill prostate cancer patients without the severe side effects brought on by chemotherapy – the only existing treatment for late stage disease.”

Mr Farrington also noted that Provenge would provide a treatment for the thousands of terminally ill prostate cancer patients unable to endure toxic chemotherapy, like his father who died with no available treatment option.

“In addition,” he wrote, “we envisioned the potential for Provenge to open doors for a whole new class of immunotherapy treatments that could possibly be effective at earlier disease stages while maintaining a better quality of life for patients than today’s treatments.”

“All of these hopes were put on hold when the FDA rejected the recommendation of its own advisory committee,” Mr Farrington pointed out.

Prostate cancer patients say woman should also be demanding an investigation into the corruption within the FDA because due to the non-approval of Provenge, Dendreon has been forced to stop the development of Neuvenge, which uses the same technology platform as Provenge, to treat breast, ovarian and colorectal solid tumors.

According to Mr Thornton, it will be years before the full impact of the FDA’s decisions is known and how many lives of cancer patients are cut short.

“For now, however,” he writes, “one thing is clear: While our lawmakers obsess over FDA “safety reforms,” no one is holding this government agency accountable for its complicity in stalling therapies for life-threatening diseases.”

That day of reckoning may be right around the corner because on December 12, 2007, Congressmen Mike Michaud (D-ME), Dan Burton (R-IN) and Tim Ryan (D-OH) sent a letter to the House Energy and Commerce Committee calling for an examination of the conflict of interests governing the FDA and its failure to approve Provenge, referred to as “a potentially life-saving prostate cancer drug.”

The letter notes that, “there is reason to believe that serious ethics rules were violated,” and “that these violations played a role in the subsequent FDA decision to not approve Provenge at this time.”

“We request your committee conduct a hearing to discuss the FDA’s role in this recent decision and the conflicts of interests in the agency,” the Congressmen wrote.

Filed under: 2008, Amgen, anemia drugs, cancer, Dendreon, ESAs, FDA, Johnson and Johnson, prices, Procrit, Provenge

Cancer Industry Fights To Keep Obscene Profits – Part II

Evelyn Pringle January 2008

Concern about the incentives to overuse injectable cancer drugs, created by the Medicare reimbursement system that paid a markup of 20% to 100%, caused rates to be changed to more closely align with what doctors actually paid for the drugs, and reimbursement is now supposed to amount to only 6% more than the average price paid by all doctors.

In 2005, all totaled, cancer doctors billed about $4.4 billion for chemotherapy and anemia medications, down from $5.6 billion in 2004, and Medicare covered 80% of the bills, according to a report by Alex Berenson in the June 12, 2007, New York Times.

Since the new reimbursement rates went into effect, cancer doctors have been lobbying Medicare officials and lawmakers to raise the prices paid for drugs, and some physicians say that doctors responded to the changes by performing treatments that got them the best reimbursement, regardless of whether the treatment benefited the patients or not.

In general, oncologists make money by providing chemotherapy, even when it has little chance of success. With the new limits on profits, some doctors are performing chemotherapy more often or installing multimillion-dollar imaging machines where they profit when patients receive diagnostic scans, according to the report in the Times.

“There’s pretty good evidence at this point,” Dr Richard Deyo, professor of medicine at the University of Washington and an expert on health care spending, told the Times, “that there are plenty of patients for whom there’s little hope, who are terminally ill, whom chemotherapy is not going to help, who get chemotherapy.”

Dr Robert Geller, an oncologist in private practice from 1996 to 2005, before becoming a senior medical director at Alexion, a biotech company, told the Times that, as long as oncologists continue to be paid by the procedure instead of for spending time with patients, they will find ways to game the system, regardless of how much money they make or lose on prescribing drugs.

“People go where the money is, and you’d like to believe it’s different in medicine, but it’s really no different in medicine,” Dr Geller said. “When you start thinking of oncology as a business, then all these decisions make sense.”

Some doctors are also now requiring cancer patients to make co-payments, which can amount to hundreds of dollars a month. Medicare calls for a 20% co-pay for chemotherapy drugs, but before the reimbursement cuts in 2005, doctors often forgave the co-pays.

In the spring of 2007, reports appeared in the media about cancer doctors receiving rebates of millions of dollars if they purchased bulk supplies of anemia drugs. Doctors were purchasing the drugs directly from Amgen and Johnson & Johnson and then collecting payments from Medicare and private insurers above the price they paid.

The drugs, known as Erythropoiesis Stimulating Agents, or ESA’s, are administered in a doctor’s office. According to the FDA, ESA’s are approved to treat anemia in patients with chronic kidney failure and in patients with cancer whose anemia is caused by chemotherapy, to reduce need for blood transfusions.

On May 9, 2007, a New York Times article titled, “Doctors Reap Millions for Anemia Drugs,” by Alex Berenson and Andrew Pollack, reported that documents given to the Times showed that at one practice in the Pacific northwest, a group of 6 cancer doctors received $2.7 million from Amgen for prescribing $9 million worth of drugs in 2006.

The FDA-approved labeling for ESA’s says patients should have a hemoglobin level of 10-12 grams per deciliter of blood, and patients are considered to need treatment if their levels fall below 10. Doctors determine whether a patient is anemic and decide on ESA dosing by measuring how much hemoglobin is present in a patient’s red blood cells.

The ESA’s approved for cancer patients are made by Amgen and sell under the brand names Procrit and Aranesp. Although Amgen manufactures Procrit, the firm licenses a Johnson & Johnson subsidiary to sell it.

Len Lichtenfeld, deputy chief medical officer for the American Cancer Society, told United Press International, “Probably more than a billion dollars is spent on erythropoietin each year, which makes it one of the most expensive cancer drugs.” A six-month course of treatment per patient can cost more than $10,000.

In November 2006, the FDA issued a public health advisory on all ESA’s, based on a study in the New England Journal of Medicine, which found that patients treated with Procrit, whose hemoglobin levels were raised above the FDA-recommended level, had a higher risk of heart attack, heart failure, stroke or death.

However, in fact, Johnson & Johnson had halted several studies of Procrit in cancer patients in 2003, after they experienced a higher than expected number of blood clots, according to the January 26, 2007, New York Times.

ESA’s are not FDA approved for use with anemic cancer patients who are not undergoing chemotherapy, but doctors have been administering the drugs off-label for that condition. To increase off-label sales, the drug companies used direct-to-consumer advertising to claim that ESA’s could restore energy and reduce fatigue in chemotherapy patients.

However, the FDA says there has never been any evidence to support claims that ESA’s could increase energy or ease fatigue in patients undergoing cancer treatment.

In January 2007, Amgen itself released the results of study conducted in hopes of supporting the approval of Aranesp for use with cancer patients who were not receiving chemotherapy which found that Aranesp did not reduce the need for transfusions and showed an increase in mortality in patients receiving Aranesp by the end of 16 weeks by a statistically significant amount, compared to patients who did not receive the drug.

In March 2007, Representative, John Dingell, (D-MI) chairman of the House Committee on Energy and Commerce, sent letters to Amgen and J&J, saying that the off-label use of the drugs “appear to cause increases in blood clots, seem to grow tumors and are associated with significantly higher mortality rates than placebo,” and told the drug makers to stop all DTC advertising and physician incentives until the FDA determines whether any measures “need to be taken to protect the public from unnecessary risks to human life from these products.”

In March 2007, the FDA added black box warnings to the labels about tumor progression and a decreased survival in patients undergoing cancer treatment. On March 9, 2007, the agency issued a public health advisory to warn doctors treating patients with kidney disease or cancer not to push hemoglobin levels over 12 grams per deciliter of blood.

The FDA again warned that ESA’s were not indicated for anemic cancer patients not undergoing chemotherapy and that mortality was increased when ESA’s were used by this population. The FDA pointed out that ESA’s are not approved for treatment of the symptoms of anemia, such as fatigue in patients with cancer.

During a March 9, 2007, press briefing, Dr Karen Weiss, deputy director of the Office of Oncology Drug Products, said the FDA became concerned after receiving the results from several trials evaluating the aggressive use of ESA’s to raise hemoglobin levels higher than listed on their approved labels.

In the March 10, 2007, Wall Street Journal, Dr Weiss was quoted as saying, the “bulk of the data that has raised concerns” came when patients were given higher doses, whether they were experiencing anemia from kidney disease or cancer treatment.

The evidence is that “this type of strategy is not beneficial and in fact has some evidence of harm,” she said.

On April 10, 2007, The Wall Street Journal reported that Amgen conducted some studies
which failed to show that the use of Aranesp improved a patient’s quality of life. On May 10, 2007, the Journal reported that J&J had “urged” doctors to enroll patients in “mini” trials using a once-a-week 40,000-unit dose of Procrit instead of three 10,000-unit doses a week.

There were $500 million a year in sales from doctors who prescribed Aranesp “off label” to treat anemia in cancer patients who were no longer receiving chemotherapy, according to the Journal.

On May 10, 2007, the FDA’s Oncology Drug Advisory Panel held a meeting and voted 15-2 in favor of new restrictions for the use of ESA’s, and 17-0 in favor of requiring the drug makers to conduct new clinical trials.

But on May 11, 2007, Bloomberg News reported that the FDA was only given limited access to results from company studies on the drugs. Amgen informed the FDA that the study data requested prior to the meeting of the advisory panel did not belong to the company and because the studies were conducted by third party researchers, Amgen did not have access to the data.

Amgen claimed that attempts were made to obtain the data and informed the FDA that the company would not be able to meet the deadline for submission to the FDA for review prior to the meeting on May 10, 2007.

FDA documents show that three years earlier, at a public meeting of the Advisory Committee on May 4, 2004, Amgen had claimed that 5 studies were being conducted to further investigate the risks of ESA’s in cancer patients, including 4 independent, third-party-sponsored clinical trials.

However, Amgen did not initiate discussions with the independent researchers to obtain the primary data for the studies until several months before the May 2007 advisory panel meeting, according to the FDA.

The FDA wanted the primary data in order to perform its own independent analysis of the results, since the studies were being used by Amgen to address safety issues that were raised by the May 2004 panel.

Concerns over the over-prescribing of ESA’s and the adverse effects on cancer patients prompted the Centers for Medicare and Medicaid Services to review Medicare coverage of their use. On May 14, 2007, CMS released its proposed coverage decision memorandum regarding the clinical conditions for Medicare reimbursement for ESA’s.

CMS found that increased thrombotic-vascular disease, tumor progression, and decreased survival occurred with ESA used to prevent or treat anemia secondary to cancer, cancer chemotherapy, or radiotherapy or to improve tissue hypoxia in an attempt to enhance tumor sensitivity to therapy.

When considering Medicare coverage of ESA’s, CMS opened the issue up for comments, and several commenters noted that it had been difficult if not impossible to obtain access to primary data from ESA clinical trials, making it difficult to conduct an independent analysis of the data.

Dr Marcia Angell, senior lecturer in Social Medicine at Harvard Medical School and former Editor in Chief of the New England Journal of Medicine, expressed concern about the lack of transparency and access of clinical trial data on ESA’s and stated in part:

“Medicare should have access to all the clinical trial information that the FDA has. Currently, companies seeking marketing approval must submit to the FDA all trials, not just the positive ones, but the agency generally does not share this information without the permission of the sponsoring company. That puts the proprietary interests of drug companies ahead of the public interest. Medicare should require full disclosure from the FDA as a condition of its support.”

Many commentators supported non-coverage for treatment of anemia in cancer patients not related to chemotherapy, stating that this was the setting in which much of the adverse outcomes were reported.

According to the CMS report, some beneficiaries with cancer stated that they had received ESA therapy continuously for years, and others stated that they continued to receive ESA’s even after their cancer was in remission.

The agency noted that there was also no evidence to support the off-label use of ESA’s in the treatment of anemia associated with radiotherapy. “The evidence reviewed and the comments received support the determination that ESA’s are not reasonable and necessary for the treatment of anemia associated only with radiotherapy,” the CMS report states.

On July 30, 2007, CMS released a final coverage determination which said that Medicare would cover the drugs for chemotherapy patients only if their hemoglobin levels were less than 10 and coverage would stop if it exceeds that level after 4 weeks of treatment.

In the Decision Memorandum, CMS determined that ESA treatment was not reasonable and necessary for conditions that include: any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis; anemia associated with the treatment of acute and chronic myelogenous leukemias, or erythroid cancers; anemia of cancer not related to cancer treatment; patients with erythropoietin-type resistance due to neutralizing antibodies, and anemia due to cancer treatment if patients have uncontrolled hypertension.

Additionally, CMS will only provide coverage for ESA treatment for the anemia secondary to myelosuppressive anticancer chemotherapy in solid tumors, multiple myeloma, lymphoma and lymphocytic leukemia, if the hemoglobin level immediately prior to initiation or maintenance of ESA therapy is below 10.

Under the old policy, Medicare allowed doctors to get paid even if cancer patients exceeded the recommended hemoglobin levels but normally physicians only transfuse patients when the hemoglobin level approaches or drops below 8, so the use of ESA’s should begin at a level most likely to prevent the hemoglobin from dropping to 8, according to the CMS report.

CMS reiterated the FDA’s warning that ESA’s increased the risk for death and serious cardiovascular events in trials when administered to target hemoglobin greater than 12, as well as an increased risk of serious arterial and venous thromboembolic events, including myocardial infarction, stroke, congestive heart failure and hemodialysis graft occlusion.

In the midst of all the complaining about the reduced coverage rates, on August 31, 2007, Senator Charles Grassley (R-Iowa), ranking member of the Senate Committee on Finance, sent a letter to Amgen CEO Kevin Sharer requesting information on the company’s rebates to health care providers.

The letter notes that the overuse of ESA’s is not only a financial concern, but also a major patient safety concern, given that recent clinical studies have identified increased risks of death, blood clots, strokes, heart attacks and tumor growths when ESA’s are given in higher than recommended doses.

As part of the Committee’s ongoing inquiry into the impact of pricing practices on the utilization of ESA’s, the Senator asked Amgen to provide:

(1) the total, average amounts and range of rebates made to physicians, group practices, physician clinics, hospital outpatient departments, skilled nursing facilities and home health agencies which purchased Aranesp and/or Epogen for calendar years 2004, 2005 and 2006 by state; and,

(2) the number of physicians, group practices, physician clinics, hospital outpatient
departments, skilled nursing facilities and home health agencies in each state which received rebates for Aranesp and Epogen in calendar years 2004, 2005 and 2006.

“As a preliminary response to this request,” the letter instructed, “identify the five physicians, group practices, physician clinics, hospital outpatient departments, skilled nursing facilities and home health agencies that received the highest rebate payments in each state in calendar years 2004, 2005 and 2006.”

Amgen’s latest SEC filing shows that Aranesp sales fell to $460 million for the 3rd quarter of 2007, compared to $720 million in the same period last year, and overall profits are down 82%. On October 17, 2007, Bloomberg News reported that Amgen has lost $18 billion in market value this year.

Not surprisingly, on November 13, 2007, the Wall Street Journal reported that Amgen was pouring millions of dollars into a lobbying campaign in an attempt to get Congress to change the Medicare coverage decision.

“The push,” the Journal says, “underscores Amgen’s dependence on Epogen and Aranesp, which together accounted for 48% of its revenue last year — and the fact that the federal government pays for the biggest share of Epogen.”

Amgen spent $9 million in the first half of 2007, nearly twice the amount that was spent in the previous 6 months. The company has a dozen in-house lobbyists and more than 100 external lobbyists, including former aides to Democratic House Speaker Nancy Pelosi and former Republican Senate Majority Leader Bill Frist, the Journal reports.

California Democrat Representative Pete Stark told the Journal that the integrity of Medicare decisions are at stake. If Congress overturns the new guidelines, the effect would be to tell the “industry they can spend millions of dollars and hire lobbyists all over town to push Congress to overrule sound science,” he warned.

Back on August 17, 2007, Fierce Biotech pointed out that Amgen had racked up $10.2 million in lobbying bills in 2006, “and is now second only to Pfizer in the amount of contributions it makes to federal candidates and parties.”

On November 9, 2007, Pharmalot’s Ed Silverman reported that Amgen was “funding a site called ProtectCancerPatients.org, which was devoted to overturning a recent Medicare decision to reduce reimbursement for Amgen’s big sellers, Aranesp and Epogen,” until November 9, 2007, when it disappeared.

“This website is the online headquarters of a national campaign to protect cancer patients on Medicare from a decision denying them needed medicines,” Mr Silverman quoted the site as saying.

“Our goal is to convince the Administration to reverse a recent decision which would effectively deny senior citizen cancer patients’ coverage and access to drugs prescribed by their doctors to combat anemia and reduce transfusions due to strong chemotherapy,” the site said.

According to Mr Silverman, site visitors were instructed on ways to contact their elected representatives and to write testimonials about the anemia drugs.

On November 13, 2007, the Wall Street Journal reported that J&J had launched a similar effort for its anemia-fighting drug, with a website “that allows individuals to send emails to the Center for Medicare and Medicaid Services and contact their representatives in Washington.”

The Journal noted that cancer doctors, “who benefit from Medicare’s unusually high reimbursement rate for anemia drugs, are also in Amgen’s corner.”

On that subject, it should be pointed out that the investigations by lawmakers are conspicuously missing when it comes to all the health care providers who engaged in the over-prescribing schemes for profit involving ESA’s.

The Journal reports that, unlike doctors, all patient groups are not on Amgen’s side. “I am astounded that this has been reduced to, ‘We want to protect patients,’ ” Frances Visco, president of the National Breast Cancer Coalition and a 20-year cancer survivor, told the Journal.

Ms Visco says the campaign has confused cancer patients who “feel used by this,” and she has urged Congress to reject what she calls Amgen’s “abusive” efforts. “Amgen is primarily interested in protecting Amgen,” she said in the Journal article.

All that said, the millions of dollars spent on lobbying and political contributions should not have any effect on the decision to limit coverage for ESA’s because new studies with reports of adverse effects in cancer patients using the drugs continue unabated. On November 8, 2007, the FDA announced new boxed warnings and labeling changes for ESA’s with statements about the risks that the drugs pose to patients with cancer.

In a press release, the FDA once again notes that ESA’s are approved to treat anemia caused by chemotherapy and says the new boxed warning clarifies that ESA’s should only be used when treating anemia specifically caused by chemotherapy and that ESA’s should be discontinued once the patient’s chemotherapy course has been completed.

The FDA repeats that an earlier boxed warning in March 2007 described the results of six studies demonstrating that survival was shorter and tumors progressed faster when ESA’s were used to achieve hemoglobin levels of 12 or greater in cancer patients.

For patients with cancer, the new warnings advises that ESA’s caused tumor growth and shortened survival in patients with advanced breast, head and neck, lymphoid and non-small cell lung cancer when they received a dose that attempted to achieve a hemoglobin level of 12 or greater.

The warnings also emphasize that no clinical data are available to determine whether there is a similar risk of shortened survival or increased tumor growth for patients with cancer who receive an ESA dose that attempts to achieve a level of less than 12, the hemoglobin level commonly achieved in clinical practice.

“Health care professionals need to consider the risks of increased tumor progression and decreased survival in patients with cancer when prescribing ESA’s,” said Janet Woodcock, the FDA’s deputy commissioner for scientific and medical programs, chief medical officer and acting director of its Center for Drug Evaluation and Research, in a press release.

On January 3, 2008, the FDA announced that the agency was reviewing more new data from two studies that provide further evidence of the risks of anemia drugs and show that patients with breast or advanced cervical cancers who received ESA’s to treat anemia caused by chemotherapy died sooner or had more rapid tumor growth than similar patients who did not receive the drug.

The agency notes that these studies were not among the 6 that were described in revised labeling on November 8, 2007. Taken together, all 8 studies show more rapid tumor growth or shortened survival when patients with breast, non-small cell lung, head and neck, lymphoid or cervical cancers received ESA’s, compared to patients who did not receive the treatment, according to the agency.

In its November 9, 2007, third quarter SEC filing, Amgen explains fairly clearly why the company is so worried about the Medicare coverage decision, in stating:

“The Decision Memorandum establishes the ESA reimbursement policy for Medicare and other government beneficiaries who are treated for CIA and who all together accounted for approximately 50% of the U.S. cancer patients receiving Aranesp prior to its issuance.”

Filed under: 2008, Amgen, anemia drugs, cancer, dialysis, ESAs, Johnson and Johnson, Procrit, Provenge

Jury Trials In 2008 Expected To Expose SSRI Maker’s Dirty Secrets

Evelyn Pringle January 2008

The blockbuster sales figures for the new generation of selective serotonin reuptake inhibitor antidepressants (SSRI’s), which have resulted from their promotion for so many unapproved uses, represents the most profitable off-label marketing coup in the history of modern medicine. Sales total about $21 billion a year, according to IMS Health.

However, in the end these drugs will probably also hold the title for the most lawsuits filed against drug companies for overstating their benefits while concealing their serious side effects from as far back as 20 years ago.

The SSRI’s include Prozac by Eli Lilly; Paxil marketed by GlaxoSmithKline, Zoloft by Pfizer, and Celexa and Lexapro from Forest Laboratories. Cymbalta by Eli Lilly and Effexor by Wyeth are often called SSRI’s, but they are actually serotonin norepinephrine reuptake inhibitors (SNRI’s). Wellbutrin sold by Glaxo is an inhibitor of the neuronal uptake of norepinephrine and dopamine. Several of these antidepressants now have generic counterparts.

In 2008, at least a dozen jury trials are scheduled all over the country for Paxil suicide-related cases, all of which allege that Glaxo failed to warn consumers and doctors about the known risk of suicide associated with the drug. Many of these cases will be tried by Baum, Hedlund, Aristei & Goldman, the national law firm with the longest track record of handling SSRI cases.

Going into the trials, Baum Hedlund will be armed with the largest collection of internal GSK documents, depositions of GSK employees and experts, as well as the fruits of the firm’s investigation of antidepressants and their makers for the past decade and a half.

During litigation, virtually every Paxil-related document obtained by Baum Hedlund was stamped “confidential” by Glaxo and sealed under a court order. However, through a series of legal challenges, the firm was able to unseal many of the documents, in part, by forcing Glaxo to admit that they did not contain trade secrets and should never have been sealed to begin with.

Off-label Promotion and Prescribing Drive Profits

The FDA approves drugs for uses that have been tested for safety and efficacy and includes those uses on the drug’s label. The term off-label means prescribing a drug for a use that has not been tested and proven safe and effective or for a different patient group, or at a different dose, or for a longer duration, or in combination with other drugs.

While doctors may legally prescribe a drug for an unapproved use, it is illegal for drug makers to promote off-label prescribing. Over the past 20 years, SSRI’s have been prescribed off-label to children as young as infants, the elderly and pregnant women, and for off-label uses that include insomnia, anxiety, shyness, grief, menstrual discomfort, pain, bed wetting, ADHD, dementia, impotence and restless leg syndrome, to name just a few.

To gain FDA approval to legally sell SSRI’s to kids, all the drug companies would have to do is provide two clinical studies showing that the drugs work better than a placebo in depressed children, and they can conduct 100 trials to achieve the necessary results. But after 20 years on the market, they still have not been able to give the FDA two positive studies to prove these drugs work with children, with the exception of Prozac.

Critics are quick to point out that this is certainly not for lack of trying because there have been dozens of pediatric trials conducted that show the drugs work no better than a placebo. How Prozac gained approval remains a mystery in light of the thousands of adverse events that were already recorded among children.

A study conducted at the University of Georgia and published in the June 2006 Journal of Clinical Psychiatry reviewed prescribing records for 107,000 Medicaid recipients on drugs that act on the central nervous system and found that 75% of SSRI patients received the drugs off-label and most of the time without their knowledge.

In April 2004, the CDC reported in the Journal of Women’s Health that antidepressants were the top drugs prescribed to women in doctors’ offices and outpatient departments, ahead of estrogens and progestins, antiarthritics and drugs for acid/peptic disorders.

According to another report by the CDC, during 2005, antidepressants were the most prescribed drugs overall in visits to doctors and hospitals and were even prescribed more often than drugs used to treat high blood pressure, cholesterol, diabetes and headaches.

Chemical Imbalance – Selling Sickness in the Absence of Efficacy

The standard line used to sell SSRI’s is that mental illnesses are caused by a chemical imbalance in the brain and that SSRI’s correct the imbalance. The Lexapro website even states: “Antidepressant medicines relieve the symptoms of depression by restoring chemical imbalances in the brain.”

However, “Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature,” in the November 8, 2005, PLoS Journal, by Jeffrey Lacasse, a visiting lecturer at the Florida State University, and Jonathan Leo, an Associate Professor of Neuroanatomy at Lincoln Memorial University, reports that, “there is not a single peer-reviewed article that can be accurately cited to directly support claims of serotonin deficiency in any mental disorder, while there are many articles that present counterevidence.”

In their most recent paper titled, “The Media and the Chemical Imbalance Theory of Depression,” appearing in the February 2008 issue of Society, Mr Lacasse and Mr Leo report that, “In spite of the enormous amount of money and time that has been spent in the quest to confirm the chemical imbalance theory, direct proof has never materialized.”

In fact, they advise that the Diagnostic and Statistical Manual of Mental Disorders, which almost all psychiatrists use to diagnose and treat their patients, clearly states that the cause of depression and anxiety is unknown.

Even when prescribed for their intended purpose in treating depression, many experts say SSRI’s are ineffective. One of the world’s most famous psychopharmacologists, Dr David Healy, author of “The Antidepressant Era,” and “Let Them Eat Prozac,” says that an overall review of the published clinical trial data on the new antidepressants reveals a 10% difference in the way people respond to the drugs verses a placebo.

He reports that 50% of patients taking the antidepressants showed some improvement and 40% of people taking a placebo showed improvement. And when the data from the unpublished clinical trials are added in, 45% of patients taking a placebo showed improvement.

The author of “Surviving America’s Depression Epidemic,” Dr Bruce Levine also says “legitimate science shows that these antidepressants are no more helpful for depression than a placebo or no treatment at all.”

However, most prescribing doctors have never heard about this 5% or 10% efficacy statistic, which researchers have referred to as the “dirty little secret,” because many of the studies that revealed the “secret” remained hidden for years. In fact, much of the information is still not in the public domain.

A new study in the January 18, 2008 New England Journal of Medicine reports that the makers of the new antidepressants failed to publish many of the clinical trials that were submitted to the FDA for market approval that did not show positive outcomes in patients taking the drugs.

The researchers found that a total of 37 studies were viewed by the FDA as having positive results and all but one were published. But 22 studies that were viewed as having negative or questionable results were not published and 11 were published in a way that conveyed a positive outcome.

The study compared drug efficacy inferred from the published literature with efficacy determined in the FDA reviews and found that in the published medical literature, it appeared that 94% of the trials were positive when the FDA analysis showed that only 51% were positive.

The clinical trials analyzed included the drugs, Wellbutrin, Celexa, Cymbalta, Lexapro, Prozac, Remeron, Serzone, Paxil, Paxil CR, Zoloft, Effexor, and Effexor XR.

“For each of the 12 drugs,” the researchers wrote, “the results of at least one study either were unpublished or were reported in the literature as positive despite a conflicting judgment by the FDA.”

A total of 12,564 patients participated in these trials and data from 3,449 patients were not published. Data from an additional 1,843 patients were reported in journal articles that highlighted findings that conflicted with the FDA-defined primary outcome.

For each of the 12 drugs, the researchers also found that the effect size derived from the journal articles exceeded the effect size in the FDA reviews, with the increases in effect size in the published reports ranging from 11% to 69%, with an average increase of 32%.

The literature-search strategy used for the study consisted of a search of articles in PubMed, references listed in review articles, and a search of the Cochrane Central Register of Controlled Trials.

The researchers also contacted the drug maker’s medical-information department by phone or email; and contact was also made by way of a certified letter to the company’s medical-information department, including a deadline for responding in writing as to whether the results of a study had been published. If these steps failed to reveal any publications, the researchers concluded that the results had not been published.

The researchers who conducted the study include Erick Turner, MD, Annette Matthews, MD, Eftihia Linardatos, BS, Robert Tell, LCSW, and Robert Rosenthal, PhD, from Oregon Health and Science University, Portland Veterans Affairs Medical Center; Kent State University; the University of California–Riverside, and Harvard University.

In their paper, “The Media and the Chemical Imbalance,” Mr Lacasse and Mr Leo point out the problem in the media where reporters still quote the people responsible for publishing bogus studies that have long been debunked.

“For instance,” they write, “several of the researchers involved with the studies of SSRIs in children are still cited in the press even though the following information has come out about their published studies: they downplayed the suicide risk; they exaggerated the benefits; and the papers published under their names were actually written by ghostwriters paid by the pharmaceutical industry.”

According to Dr Levine, depression is not a biochemical disorder and refers to it as a strategy used to shut down overwhelming pain. Dr Levine states that, if the strategy is used to excess, it can lead to immobilization and greater pain.

He explains that depressed people experience feelings of hopelessness and helplessness and that labeling them with a disease leads to more of the same feelings.

Instead of calling it an illness or weakness, Dr Levine says, depression can be lessened by helping patients understand that it is a normal human reaction and they can identify the source of the pain and heal.

More Disorders Equals More Profits

To expand the market, the SSRI makers have managed to create a whole new generation of psychiatric illnesses by simply padding the bank accounts of a few psychiatrists who determine the criteria for the inclusion of mental disorders in the DSM. With their inclusion in the billing bible comes the guaranteed payment for the cost of the SSRI’s and the visits to the prescribing doctor by public and private health insurance programs.

There are also a whole new slew of SSRI treatable disorders lining up for inclusion in the next DSM edition. For instance, an August 3, 2006 article by Reuters reported that, “People with ‘body dysmorphic disorder’ are 45 times more likely to commit suicide than people in the general population, a new study shows.”

“The findings underscore the importance of recognizing and treating this ‘often secretive’ psychiatric disorder,” Dr Katherine Phillips, the study’s co-author, told Reuters.

Individuals with body dysmorphic disorder, she said, have a distorted body image and think obsessively about their appearance, often for hours a day, but can be helped with drugs like Prozac or Zoloft and cognitive behavioral therapy.

On October 3, 2006, the New York Times ran the headline: “Can’t Keep From Shopping? Help Could Be on the Way,” for an article that said, compulsive buying, “in its extreme forms may be a psychiatric illness — an impulse control disorder associated with abnormal levels of depression and anxiety.”

The article discussed a study in the American Journal of Psychiatry, and the lead author, Dr Lorrin Koran, told the Times: “Many of those who come in for treatment suffer from depression, anxiety disorders and other impulse control disorders like pathological gambling and binge eating.”

She also threw in a sales pitch saying, “studies suggest that psychotherapy or medications help many compulsive buyers to stop.”

This news could potentially raise SSRI profits by 10%, because the Times says a statistical analysis of the study results found 5.5% of men and 6% of women could be afflicted.

The article also points out that compulsive buying is not yet a recognized psychiatric diagnosis, but that it is being considered for inclusion in the next edition of the DSM.

Good news for Pfizer came in the October 2006, Journal of Clinical Psychiatry, from a study led by Dr Susan Kornstein, at Virginia Commonwealth University, that claims low doses of Zoloft for 2 weeks before the onset of the menstrual period may be effective and well-tolerated for treating women with moderate-to-severe PMS.

The researchers also claim that other dosing strategies are effective, including taking Zoloft daily or waiting until symptoms begin to start taking it.

Zoloft is already approved for premenstrual dysphoric disorder (PMDD), but profits could skyrocket with widespread dissemination of this study because the researchers report that up to 60% of women suffer from PMS, while only about 5% suffer from PMDD.

On October 26, 2006, an Indianapolis Star headline warned that: “Midnight munchies can signal big problems.” The article explained that routine and heavy nighttime snacking can be a sign of eating for reasons other than hunger and more serious symptoms can point to “a little-known eating disorder called night-eating syndrome.”

But not to worry, because the researchers who did the study told the Star that Zoloft can help these poor souls as well, along with therapy to change eating and exercise patterns.

Great news for Glaxo came on October 27, 2006, when United Press International ran the headline: “Paxil helps compulsive hoarding syndrome”.

According to UPI, persons with this syndrome exhibit 3 features: failure to discard objects due to severe anxiety related to discarding what most might regard as inconsequential objects; excessive acquisition, sometimes resulting in buying sprees, and excessive clutter to the point where home and work spaces can no longer be used.

Here again, however, researchers led by Dr Sanjaya Saxena at the University of California, report that Paxil is effective in treating this dastardly new disorder.

Risks Outweigh the Benefits

Experts say that if patients were adequately informed about the long list of side effects associated with SSRI’s and their dubious efficacy before they took the first pill, they would be more than a little skeptical about whether their benefits outweigh the risks.

The SSRI labels now warn patients not to take them with common over-the-counter medications such as aspirin and many other pain relievers, or with cold remedies or herbal supplements like St John’s Wort, or with alcohol.

SSRI side effects include suicidality, violence and homicide, birth defects, abnormal gastrointestinal and uterine bleeding, a decrease in bone density, fertility problems, sexual dysfunction, severe withdrawal and the life-threatening condition, serotonin syndrome.

According to the SSRI labels, symptoms of serotonin syndrome include mental status
changes such as agitation, hallucinations, or coma; autonomic instability like tachycardia, labile blood pressure and hyperthermia; neuromuscular aberrations such as hyperreflexia and incoordination, and gastrointestinal symptoms of nausea, vomiting and diarrhea.

All the current labels say that anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania have been reported in adult and pediatric patients treated for major depressive disorder, as well as for other indications, both psychiatric and non-psychiatric.

The labels also report that infants exposed in the womb have developed complications requiring prolonged hospitalization, respiratory support and tube feeding upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying.

The labels note that these features are consistent with either a direct toxic effect or possibly a drug discontinuation syndrome and say it should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.

On December 8, 2005, the FDA issued a public health advisory to report that women who take Paxil in early pregnancy are at an approximately 2-fold increased risk of having an infant born with a cardiac defect compared to the general population.

Also cited on the labels is a study finding that infants exposed to SSRI’s in late pregnancy showed a 6-times greater risk of developing the lung disorder known as persistent pulmonary hypertension of the newborn (PPHN), a condition that, despite treatment, results in the death of approximately 10 to 20 percent of affected infants.

In December 2006, a Journal of Clinical Psychiatry study reported that about seven of every ten people who take antidepressants have impaired driving ability and that 16% have severe motor impairments after taking the drugs.

A short list of the adverse effects listed on the various SSRI labels as “frequent,” and occurring on one or more occasions in at least 1 out of every 100 patients, includes light-headed feeling, appetite increased, increased weight, heartburn, abdominal cramp, gastroenteritis, allergy, pain in limb, fever, hot flushes, chest pain, lethargy, irritability, concentration impaired, abnormal dreams, sleep disorder, menstrual cramps, menstrual disorder, impotence, anorgasmia/orgasm abnormal, bronchitis, sinus congestion, coughing, migraine, sinus headache, vision blurred, urinary frequency and urinary tract infection.

Upcoming Jury Trials

Veteran trial lawyer, Ronald Goldman, who won one of the largest verdicts for the death of an unmarried person in Ohio state’s history last year, is leading the Baum Hedlund team in the trials.

Glaxo has good reason to fear jury trials. The first Paxil-related suicide trial resulted in a verdict for the plaintiff. The case took place in Wyoming in May 2001 and involved a man, Donald Schell, who shot and killed his wife, daughter, and infant granddaughter before turning the gun on himself, after being on Paxil for only 2 days.

The instructions given to the jury required a finding that, “Paxil was a proximate cause of Donald Schell committing the homicides and suicide involved in this litigation” and that Glaxo’s failure to test or to warn “was a proximate cause of the homicides and suicide in this litigation.”

On June 6, 2001, the jury returned a verdict in favor of the plaintiffs and the Court entered a judgment against Glaxo for more $6 million. Glaxo filed an appeal and the parties settled out of court while the appeal was pending.

Baum Hedlund has litigated over 3,000 pharmaceutical cases in the past 18 years and the firm currently has approximately 30 SSRI suicide-related cases in litigation.

Baum Hedlund served on the Plaintiffs’ Steering Committee in the first suicide-related case involving Prozac and served as lead counsel for the Plaintiffs’ Steering Committee in Paxil Products Liability Litigation. The firm is also handling SSRI-related birth defect lawsuits.

(Written as part of the SSRI Antidepressant Litigation Monthly Round-Up, Sponsored by Baum Hedlund’s Pharmaceutical Antidepressant Litigation Department)

Filed under: 2008, Baum, Glaxo, Paxil, SSRIs, suicide, Zoloft

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