The Bitter Pill

The Official Blog of UNITE – uniteforlife.org

Vaccination Profiteers Gang Up on Hannah Bruesewitz in Supreme Court

Evelyn Pringle

The American Academy of Pediatrics announced the submission of an amicus brief to the US Supreme Court on July 30, 2010, “joined by 21 partnering health organizations,” in the vaccine injury case of Bruesewitz v Wyeth, to support the powerful vaccine maker against a lone family.

Oral arguments in the case took place on October 12, 2010, but a final decision won’t be known for months. The most recent drug injury preemption case decided by the Court was also against Wyeth and the ruling came down in favor of plaintiff, Diane Levine.

The Court took the Bruesewitz case to determine whether 18-year-old Hannah, disabled by injuries she received from Wyeth’s diphtheria, tetanus and pertussis (DPT) vaccine at 6-months-old in 1992, has the right to bring a lawsuit against Wyeth after the Vaccine Court, set up by the 1986 National Childhood Vaccine Injury Act, refused compensation even though she will require life-long care and her vaccine was traced to a lot that had 65 adverse reactions including two deaths, 39 emergency room visits, and 6 hospitalizations.

After compensation was denied, the family filed suit against Wyeth in Pennsylvania and argued that the vaccine Hannah received was defectively designed and had a known safer vaccine been used her injuries could have been avoided.

Wyeth filed for summary judgment and the lower court dismissed the case holding that the 1986 vaccine law preempted all design defect claims. In March 2009, the Third Circuit Court of Appeals affirmed the ruling and the family filed a petition for review in the Supreme Court.

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Filed under: 2010, autism, Preemption, Supreme Court, thimerosal, vaccines

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

Lilly Faces Mounting Legal Battles Over Zyprexa – Part I

Evelyn Pringle November 7, 2007

Since August 2006, as part of an on-going, multistate investigative effort by approximately 30 states, Eli Lilly has received civil investigative demands or subpoenas seeking a broad range of documents relating to the company’s marketing and promotion of the antipsychotic drug
Zyprexa, and more states are expected to join the effort.

In addition, a total of ten states are now suing Lilly for Medicaid fraud to recover the cost of Zyprexa purchases for persons covered by the program, along with the past and future costs of treating Zyprexa-related illnesses. Alaska, Arkansas, Louisiana, Mississippi, Montana, New Mexico, Pennsylvania, Utah and West Virginia have filed cases thus far.

Zyprexa belongs to a new generation of antipsychotic drugs known as “atypicals” which arrived on the US market in 1994, beginning with Risperdal, marketed by Johnson and Johnson subsidiary Janssen. Other drugs in this class include Seroquel, sold by AstraZeneca; Geodon, by Pfizer; Abilify, from Bristol-Myers Squibb and Clozaril, marketed by Novartis.

For the first four years that Zyprexa was on the market in the US, it was only approved to treat adults with schizophrenia, and it was not until 2000 that the FDA approved the drug for adults in the manic phase of bipolar disorder.

However, in a matter of a few short years, Lilly turned Zyprexa into its best-selling product, despite the drug’s extremely limited approved uses, by influencing doctors to prescribe the drug off-label.

In addition to prescribing a drug for unapproved uses, off-label can mean treating an approved condition for a longer duration of time, or prescribing a drug in combination with other drugs, or at a different dosage, or to a different patient population such children or the elderly, other than those specified on the FDA-approved label.

According to Lilly’s SEC filings, the Office of the US Attorney for the Eastern District of Pennsylvania has also advised Lilly that it has commenced a civil investigation related to the company’s marketing and promotion of Zyprexa, and a “number of State Medicaid Fraud Control Units are coordinating with the EDPA in its investigation of any Medicaid-related claims relating to Lilly’s marketing and promotion of Zyprexa.”

Lilly has also received subpoenas from the Office of the Attorney General of the State of Illinois, and the Florida Office of the Attorney General, Medicaid Fraud Control Unit, asking for documents relating to sales, marketing and promotion of Zyprexa.

Lilly’s SEC filings also report that the company has received requests for information related to the company’s marketing and promotion of Zyprexa from the offices of Representative Henry Waxman, Chairman of the House Committee on Oversight and Government Reform, and Senator Charles Grassley, the ranking Republican on the Senate Finance Committee.

Collectively, the Medicaid fraud lawsuits allege that Lilly illegally influenced doctors to prescribe Zyprexa off-label to patients, including children, for conditions such as behavior and mood disorders, eating disorders, anxiety, post traumatic stress disorder, insomnia, PMS, Alzheimer’s, Tourette’s syndrome, dementia and other unapproved indications.

The lawsuits also allege that Lilly concealed the adverse effects associated with Zyprexa, including drastic weight gain, high blood sugar levels, diabetes and pancreatitis.

Other serious adverse effects known to be associated with Zyprexa include Parkinson-like symptoms, akathisia, tardive dyskinesia, dystonia, hypotension, constipation, tachycardia, seizures, liver abnormalities, white blood cell disorders and death.

The Mississippi lawsuit alleges that about 10% of Zyprexa patients have developed diabetes, some of whom are children, even though Zyprexa “has never been approved for, nor found to be effective, in the treatment of children.”

An estimated 1,500 Utah Medicaid patients who took Zyprexa have developed diabetes, according to the lawsuit filed on May 29, 2007, by state attorney general David Stallard.

Utah is seeking damages including $5,000-$10,000 for each prescription that was “not medically necessary.”

Lilly recently attempted to get the Utah case dismissed, in part by arguing that the allegations of off-label promotion and failure to warn were preempted by FDA regulations under a new rule put in place by the Bush Administration, largely viewed as a gift to the pharmaceutical industry.

In 2006, the FDA published a preamble to new prescription drug labeling rules in which it asserted that its approval of the labeling would prevent the filing of lawsuits in state courts premised on a theory that a drug company should have provided additional warnings on a drug’s label.

However, the Utah court ruled against Lilly on this issue and stated, in part: “In fields traditionally occupied by the states, such as health and safety regulation, there is a strong presumption against federal preemption,” and Lilly “has not overcome this strong presumption.”

Pennsylvania alleges that the state spent millions of dollars “for non-medically accepted indications and non-medically necessary uses of Zyprexa,” as well as “significant sums of money for the care and treatment” of patients injured by the drug.

Montana’s complaint charges that, “Lilly management participated, encouraged and authorized the unlawful payment of illegal kickbacks to physicians in order to continue generating sales of Zyprexa.”

The Montana lawsuit is asking for reimbursement on behalf of all citizens who purchased Zyprexa, and not only patients covered by public health care programs, because under the law in that state, the attorney general can request treble damages and attorneys’ fees on behalf of all consumers.

There are also several RICO class actions filed against Lilly on behalf of union insurance plans, pension funds, and other private health insurers, which accuse Lilly of violating racketeering laws and allege the drug maker engaged in illegal marketing schemes to promote the sale of Zyprexa for off-label uses and seek to recover the cost of purchasing the drug, as well as treble damages, punitive damages and attorneys’ fees.

On June 28, 2007, Lilly lost a motion for a summary judgment dismissal of the RICO claims, based on the preemption argument, when District Court Judge Jack Weinstein for the Eastern District of New York ruled against the company, In re Zyprexa Products Liability Litigation, 2007 WL 1851161.

In a written ruling rejecting Lilly’s argument that state law failure-to-warn claims are preempted, Judge Weinstein wrote that “the regulation of public health is an area traditionally occupied by the states, supporting a presumption against preemption.”

“Under the present organization of the pharmaceutical industry, the official federal Food and Drug Administration (FDA), and the plaintiffs’ bar,” he stated, “the courts are arguably in the strongest position to effectively enforce appropriate standards protecting the public from fraudulent merchandising of drugs.”

The Judge also noted that Congress had not stated an intent to preempt these claims. “The FDA cannot be allowed to usher in such a sweeping change in substantive law through the back door,” he wrote.

The Medicaid fraud lawsuits allege that many children have been turned into customers for the off-label prescribing of Zyprexa. A recent October 7, 2007, report from the Florida Agency for Health Care Administration entitled, “The Use of Antipsychotic Medications with Children,” found that pediatric use of antipsychotics increased in the late 1990′s and early 2000′s, largely due to the arrival of the atypicals on the market.

The report noted that one study documented a 75% increase with commercially insured children aged 0 to 17 from 1997 to 2001, and another study of the managed care population from 1996 to 2001 found a 127% increase among children aged 0 to 18.

The study also reported that antipsychotic use in the Medicaid populations was three to four times higher than commercial populations in the late 1990′s, and in one program in the Midwest, the rate of prescriptions grew 304% between 1996 and 2001.

The authors said the analysis showed that the drugs are being used to treat a broad spectrum of disorders, and some of the disorders, such as attention deficit hyperactivity disorder and major depression, “clearly do not call for antipsychotic treatment.”

In the 0 to 5 age group, the study found that more than 53% of the drugs were prescribed for ADHD, even though antipsychotic use with children under 6 “should be considered only in very rare circumstances.”

A report in the May 10, 2007, New York Times revealed some of the known adverse events that occurred in children who were prescribed antipychotics in 2006 alone. The FDA received reports of 29 children dying, and at least 165 other serious side effects in children, where an antipsychotic was listed as the primary suspect, according to the Times.

The FDA acknowledges that its reporting system only picks up between one and ten percent of the adverse events that take place, which means the number of deaths and injuries above must be multiplied many times over to obtain an accurate estimation of how many children have been harmed by the drugs.

Filed under: 2007, antipsychotics, Eli Lilly, Fraud, MEDICAID, Preemption, Zyprexa

No Preemption for J&J against Charite Spine Surgery Victims

Evelyn Pringle April 25, 2007

According to Johnson and Johnson’s SEC filings, as of December 31, 2006, there were 100 lawsuits pending against the company involving the Charite artificial spinal disc, seeking “substantial compensatory and, where available, punitive damages.”

The J&J subsidiary, DePuy Spine, has marketed the Charite since the disc was FDA approved for sale in the US in October 2004, to treat patients who have degenerative disc disease at one level in the spine.

In a nutshell, the lawsuits allege that the Charite is defective, it was improperly marketed, and J&J failed to adequately warn doctors and consumers about the dangers of the disc.

In March 2006, J&J filed a motion for summary judgment in attempt to have 4 lawsuits dismissed in the Superior Court in Bristol, Mass, using a legal defense known as preemption where a device maker cannot be sued if the FDA has approved the device.

Its ironic that J&J would try to use this argument when experts say the fault lies with the FDA for approving the Charite to begin with based on one 2-year noninferiority trial that sought only to show that it worked as well as the Bagby and Kuslich (BAK) cage used in spinal fusions, which had already been abandoned due high failure rates.

And even when compared to the outdated surgery, the disc worked no better in relieving pain and most Charite patients were still taking narcotic pain drugs 2 years later.

On April 11, 2007, Judge Susan Garsh denied J&J’s motion and noted that the plaintiffs alleged that DePuy made specific performance claims to obtain FDA approval that the device failed to achieve and “there is evidence to support the device does not perform in the manner which DePuy represented to the FDA that it must perform,” she wrote.

According to the lawsuits, Charite patients were provided materials by DePuy that stated: “The Charite Artificial Disc has a clinical history spanning 17 years. Its safety, efficiency and remarkable durability have been proven through thousands of implants worldwide.”

DePuy also promoted the disc with the phrase: “Natural Motion is Back.”

J&J claims that replacement surgery will alleviate chronic back pain, permit natural movement and improve the patient’s ability to function under the premise that segmental mobility of the spine will improve, as has been the case with hip and knee replacement.

J&J’s main selling point is that disc replacement is more effective than lumbar spinal fusion surgery, where the damaged disc is removed and the vertebrae are joined together using bone grafts, metal screws and/or cages and motion can no longer occur in that area.

However, critics point out that in many of the surgeries listed as successes, the Charite only worked after the auto-fusing of bones together, similar to spinal fusion surgery, which eliminates the possibility of natural motion that leads patients to chose the costly replacement surgery to begin with.

A long line of studies show the odds for revision surgery in Charite patients are high. Back in 1996, Cinotti, David et al, analyzed the follow-up on 46 patients and eight patients had undergone subsequent fusion surgery. “The main cause of poor outcomes appear to be an inappropriate selection of patients undergoing disc replacement,” the authors concluded.

In 1997, Lemaire, Skalli, et al, reported on 105 patients with average follow-up of 51 months and found that fifty patients or 48% had undergone at least one operation.

A 1999 study by Zeegers, Bohnen et al in the Netherlands reported the 2-year results for 50 patients and found 12 patients, or 24%, needed re-operation.

In a more recent study from the University Medicine in Berlin (2005), Putzier, Funk et al evaluated 71 patients who received implants between 1984 and 1989, and of the 53 patients available for examination, 12, or 23%, had undergone surgical fusion.

But there were warnings that the Charite was not all it was cracked up to be even before it was approved. In April 2003, the Spine Journal published the paper, “Total Disc Replacement for Chronic Low Back Pain: Background and a Systematic Review of the Literature,” that stated: “There is no evidence that disc replacement reliably, reproducibly, and over longer periods of time fulfils the three primary aims of clinical efficacy, continued motion, and few adjacent segment degenerative problems.”

Some experts say the Charite itself is the problem. On October 23, 2006, the Street.com reported that researchers at the University of California at Irvine claim the device maker made a crucial mistake when designing the disc that explains why the replacement surgery has resulted in repeated failures with “catastrophic consequences” for patients.

“They’ve based their center of rotation on a disc space that is in front of the spinal canal,” Dr Charles Rosen, a Cal-Irvine spine surgeon, told the Street.

According to Dr Rosen, the makers overlooked the spine’s normal function by creating an “artificial center of rotation” in a space that lies in front of the spinal canal instead of behind it and has compromised the body in the process.

“You have a center of rotation that’s normally there, and they falsely impose another,” he told the Street. “You can’t have two because they will neutralize each other. Something has to give.”

“To give,” he says, “either the back part of the device breaks or the front part dislocates.”

J&J has a lot of money riding on the Charite and if it turns out that Dr Rosen is right, its January 1, 2006, projection the total spine market will bring the company $9 billion by 2010 will go right down the tubes.

Spine surgery is a multi-billion dollar industry. According to the August 5, 2006 LA Times, at least $3.2 billion was spent in the US on spinal fusion in 2005, and Medicare payments to hospitals for implant surgery have risen about 40%, in the past 2 years, from $10 billion to $14 billion, according to the September 26, 2006, New York Times.

However, serious questions are being raised about whether doctors and hospitals are practicing surgery for profit, especially since the revelation that surgeons are investing in companies that make the devices and hardware used during spine surgery.

On December 30, 2006, Reed Abelson reported in the New York Times that over the past couple of years, about 30 start-up companies have begun selling spine devices and hardware and about a dozen have doctors investors.

“Because most of the companies are private and the relationships are not publicly disclosed,” he wrote, “there is no way to know how many spine surgeons around the country are partial owners of device makers.”

Stan Mendenhall, editor of the newsletter, Orthopedic Network News, told the Times that the spine device market has doubled in the last 3 years and there are now about 100 companies and doctors have ownership in some of the newest firms. And there are apparently plenty of profits to spread around because the report says a single screw sells for around $1,000 or 10 times the cost of making it.

Back on June 28, 2006, the Times revealed another funneling scheme set up by doctors and device makers when it reported that, “doctors in private practice have set up tax-exempt charities into which drug companies and medical device makers are, with little fanfare, pouring donations — money that adds up to millions of dollars a year.”

“The tax-exempt money also sometimes flows to the for-profit medical groups affiliated with the charities,” the Times wrote, “sometimes covering business expenses or even paying parts of the salaries of doctors.”

For example, the Times revealed that the tax-exempt, “Blue Ridge Bone and Joint Research Foundation,” headed by Dr Joseph Moskal, an orthopedic surgeon, received $75,000 from DePuy in the year ending July 31, 2004, and then paid $30,000 of that money to the for-profit Roanoke Orthopaedic Center, where Dr Moskal practices, to defray the costs of a fellowship program there.

The Department of Justice made it known that J&J’s relationships with doctors are under investigation in June 2006, when it served subpoenas and search warrants on DePuy, demanding copies of consulting contracts, professional services agreements, and documents that evidence the company’s arrangements with orthopedic surgeons.

Filed under: 2007, Charite, DePuy, Johnson and Johnson, medical devices, Preemption

Novartis Failed to Warn About Elidel Cancer Link

Evelyn Pringle December 28, 2006

Most lawsuits in which drug makers have tried to use preemption to dismiss failure-to-warn claims have been against companies accused of failing to warn about the risk of suicide associated with antidepressants known as selective serotonin inhibitors or SSRIs.

However, a case in Pennsylvania against Novartis, involves a toddler who developed cancer due to a failure-to-warn about the risks associated with the topical drug Elidel. In an important decision sure to have an impact on many other cases in the US, on October 16, 2006, a US District Court in Eastern Pennsylvania refused to grant the drug maker’s preemption motion in, Perry v Novartis Pharma Corp, — F Supp 2d —, 2006 WL 2979388.

Elidel was approved by the FDA on December 13, 2001, to treat atopic dermatitis, commonly known as eczema, in a cream applied directly to the skin, for persons over the age of two.

Elidel belongs to a class of immunosuppressant drugs known as calcineurin inhibitors. At the time of its approval, there were already concerns about an association between Elidel and cancer because other calcineurin inhibitors that were used to treat organ transplant patients were known to increase the risk of cancer and lymphoma, and carried a Black Box warning to that affect.

At the time of its approval, Elidel had also been found to increase the risk of cancer in animals when administered at high doses.

Because of its concerns about cancer, the FDA placed restrictions on Elidel and approved it only for short-term and intermittent use, and as a second-line of treatment to be used only when traditional therapies such as corticosteroids were found to be ineffective.

Following FDA approval, Novartis aggressively promoted Elidel, and as a result millions of prescriptions were written, many of which were off-label, meaning outside the approved indications and limitations specified on the label.

In the case of young Andreas Perry, the prescription was off-label in that no other treatment had been tried for his eczema prior to prescribing Elidel. Six months after he began using the cream, in October 2003, Andreas was diagnosed with lymphoblastic lymphoma, a form of cancer.

Although his eczema was annoying and uncomfortable, it was not life-threatening and his parents never considered for a moment that Andreas would develop cancer from a medicated cream prescribed for a toddler who was barely 2-years-old.

But on the other hand, Novartis can hardly claim ignorance about the link between cancer and Elidel because when the reports of cancer started coming in, the FDA began openly discussing the need to strengthen the warnings and the fact that the drug was being over-prescribed off-label to children for unapproved uses.

In October, 2003, the FDA’s Pediatric Advisory Subcommittee to the Anti-Infective Drugs Advisory Committee met to evaluate the cancer rates among pediatric patients treated with calcineurin inhibitors and discussed the possibility of changing the label to specifically warn against their use in patients under two.

At the hearing, a pharmacist and safety evaluator reported that more than 3.2 million prescriptions for Elidel had been dispensed by August 2003, with 17% of those prescriptions written “off-label” for children under the age of 2, and representing 22% of the adverse event reports for the drug.

On February 15, 2005, the Committee met again amidst even more reports of off-label use of calcineurin inhibitors with children which caused concern for many members of the Committee. The briefing memorandum for the meeting reported that more than 500,000 prescriptions had been written for children under 2 during a one year period between June 2003 and May 2004.

At this meeting, the panel voted to recommend that a “Black Box” warning be added to the label about the increased risk of cancer associated with the topical use of the two calcineurin inhibitors, Elidel and Protopic, and also about the lack of long-term safety data on the drugs.

The FDA issued a public health alert on March 10, 2005, stating in part, “Animal studies have shown that three different species of animals developed cancer following exposure to these drugs applied topically or given by mouth, including mice, rats and a recent study of monkeys.”

“Based on the advice of the FDA Pediatric Advisory Committee, which met on February 15, 2005,” the alert advised, “FDA will require labeling changes for Elidel and Protopic, including the placement of a boxed warning about the potential cancer risk.”

However, this case illustrates another situation like Vioxx and the SSRIs, where the FDA is as much to blame as Novartis for patients being injured after the danger was known, because the agency knew that a “Black Box” warning should be added immediately but allowed the drug company to dilly-dally around for nearly a year before adding the cancer warning on January 19, 2006.

In their lawsuit, the Perrys allege that despite Novartis’s knowledge of the association between Elidel and cancer, Novartis promoted it as safe for the treatment of eczema. It also alleges that the drug was advertised, marketed, and promoted as safer than traditional corticosteroid treatments, in conscious disregard of the limitations that the FDA placed on its approval, and that these actions contributed to the inadequacy of the warnings.

In response, Novartis filed a motion to dismiss the failure-to-warn claims based on the FDA’s new preemption policy. On January 18, 2006, the FDA issued new regulations regarding the labeling of prescription drugs, supposedly to provide doctors and patients with clearer information. However, in the preamble to the new rules, the FDA inserted the claim that State tort lawsuits alleging a failure-to-warn about risks associated with drugs approved by the FDA are preempted by federal law.

After failing at efforts to implement tort reform, this move is largely seen as the Bush administration’s last ditch attempt to immunize the pharmaceutical industry with policies written by politically appointed officials carefully planted at the top of the nation’s regulatory agencies.

Right from the start, it should be noted that State failure-to-warn lawsuits against drug companies have existed for over a century. Back in 1852, in the New York case of, Thomas v Winchester, 1852 WL 4748, the court stated, “A dealer in drugs and medicines, who carelessly labels a deadly poison as a harmless medicine, and sends it so labeled into market, is liable to all persons, who, without fault on their part, are injured by using it as such medicine in consequence of the false label.”

Second, if Congress wanted to preempt State tort claims it would have done so. Congress was fully aware of these lawsuits in 1934, when it enacted the Food, Drug and Cosmetic Act, and chose not to include a private right of action for damages in the Act after determining it was “unnecessary,” because a “common-law right of action exists.”

For as former Chief Counsel of the FDA, Margaret Porter, wrote in 1997, “FDA product approval and state tort liability usually operate independently, each providing a significant, yet distinct, layer of consumer protection.” The Lohr Decision: FDA Perspective and Position, 52 Food & Drug. L.J. 7, 11 (1997).

While it may be true that the FDA approves a drug’s label when it approves the drug, the label is not fixed in stone. It is well known that drugs are approved based on very limited clinical trials and understood that there is a strong likelihood that new risks will be identified as a drug is widely prescribed in the general population.

For this reason, under federal regulations, a drug maker’s duty to provide warnings to health care professionals and consumers continues as long as a drug is on the market. In its own regulations, the FDA itself has noted that labeling does not always contain the most current information because “advances in medical knowledge and practice inevitably precede formal submission of proposed new labeling by the manufacturer and approval by the FDA.”

And that’s why federal regulations put the responsibility on the drug company stating, “labeling shall be revised to include a warning as soon as there is reasonable evidence of an association of a serious hazard with a drug; a causal relationship need not have been proved.”

In the brief filed in support of its motion, Novartis contends that companies rarely, if ever, change labels under this provision because they know that they ultimately need to obtain FDA approval for the change.

The truthful explanation for its refusal to comply with this provision, would be that Novartis knew that adding a warning would have resulted in a drastic reduction in the profits that the company was enjoying from the “off-label” sale of Elidel to children.

When attempting to use the preemption defense, as a starting point, Novartis, and every other drug company, should be required to explain why it would have been difficult to add a specific warning to the label.

In an amicus brief submitted by the FDA that sides with Novartis overall, the agency quotes regulations and describes the simple procedure used to add a warning, and it takes a whole 30 days. According to the FDA:

“If the manufacturer of a non-generic prescription drug wishes to add or strengthen a warning, the manufacturer may provide FDA with a supplemental submission regarding the proposed labeling change, providing a full explanation of the basis for the proposed change.

“If FDA has not rejected the supplement within 30 days after its submission, the manufacturer may distribute the drug with the new proposed labeling.”

The FDA’s brief also states: “If a drug manufacturer has “reasonable evidence of a causal association” between the use of a drug and a “clinically significant hazard,” the manufacturer has an obligation to seek FDA approval for a labeling change, in order to add a warning of the new potential hazard.”

As far as “reasonable evidence” goes, it would not take a rocket scientist to figure out that if 3 species of animals were developing cancer from Elidel, infants and toddlers weighing between 6 and 30 pounds would probably do so as well.

In its brief, Novartis relies on the FDA’s argument in the preamble that it interprets the FDCA “to establish both a ‘floor’ and a ‘ceiling,’” and thereby preempts state laws imposing greater safety requirements.

However, in the FDA’s own words, liability will only attach, “if the additional statement is unsubstantiated or otherwise false or misleading,” which is certainly not the case with Elidel.

In their brief, the Perrys argue that the FDA does not impose a “ceiling” on truthful, substantiated risk information, which is precisely the type of warning they sought.

In this case, the FDA has never rejected stronger warnings for Elidel and the court held that preemption would only apply if a specific warning about pediatric cancer had been considered and rejected.

In addressing the claims in the FDA’s brief, the opinion states: “To be sure, because of its expertise in the area, the FDA’s construction of its own regulations is likely to carry great weight.”

“But where an interpretation has changed frequently in significant respects,” it points out, “the persuasive force of the argument diminishes.”

The court went on to explain that even if the preamble did represent a change of policy with the force of law, it would not apply to this case. “The FDA,” it said, “cannot retroactively absolve Novartis of a duty it may have owed the Perrys in 2003.”

The opinion also states that “a finding of preemption here will foreclose a remedy that was traditionally available and for which federal law provides no substitute.”

In conclusion, citing a September 23, 2006, New York Times report by Gardiner Harris, the court said, “given the recent concerns about the effectiveness of the FDA’s safety monitoring of recently approved drugs, . . . the availability of state law tort suits provides an important backstop to the federal regulatory scheme.”

Filed under: 2006, cancer, Elidel, Novartis, Preemption

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