The Bitter Pill

The Official Blog of UNITE – uniteforlife.org

Evelyn Pringle July 24, 2007

On July 27, 2007, Bush’s Big Pharma friendly CDC issued a press release clearly aimed at increasing the sale of SSRIs to pregnant women. “Use of certain antidepressants, selective serotonin-reuptake inhibitors most commonly known as SSRIs, during pregnancy does not significantly increase the risk for most birth defects,” the CDC wrote.

The press release cited a new CDC study released in the New England Journal of Medicine and further stated, “a second study on SSRI and birth defects, also published in the June 28 issue of NEJM, did not find such an association with birth defects overall, but did find significant associations between specific SSRIs and several birth defects.”

Since the CDC put out the press release, hundreds of headlines have flooded the internet citing the new studies as proof that there is a low risk of birth defects with SSRI use during pregnancy, and the results of the studies have been reported as breaking health care news by every major media outlet in the US.

The pharmaceutical industry as a whole has spent a fortune buying influence in the media since 1997, when the government lifted restrictions on direct-to-consumer advertising.

In an article titled, Physicians and Bribery, published by News Target on July 7, 2005, Dani Veracty says the real story about prescription drugs is not being told because the drug makers are controlling the budgets of the major media companies by pumping hundreds of millions of dollars into TV, magazine, newspaper and online advertising.

“Because of this,” he states, “the media companies out there don’t want to say anything bad about these prescription drugs.”

In the July-August Columbia Journalism Review, contributing editor Judy Lieberman, reported that at the end of 2004, drug-company ad revenue for Time Magazine totaled $67 million; for Newsweek $43 million; and for The New York Times took in $13 million.

By 2004, she reported, advertising revenues for the five networks including CNN and Fox news was $1.5 billion.

The drugs in the NEJM studies included Prozac by Eli Lilly, Zoloft from Pfizer; Paxil by GlaxoSmithKline, Celexa and Lexapro from Forest Labs; Luvox by Solvay, Effexor by Wyeth, and generic SSRI makers include Barr Pharmaceuticals, Ranbaxy Labs and Genpharm.

Prior to the arrival SSRIs on the market, depression was estimated to affect only 100 people per million and patients with depression sought help from a medical professional trained in psychiatry and the treatment of disorder.

However, the rate of depression is now estimated to be in the range of 50,000 to 100,000 cases per million, or between a 500 to 1,000-fold increase, according to Jane Currie in the Marketization of Depression, in the May 2005 journal Women and Health Protection.

In April 2004, the CDC reported that antidepressants topped the list of drugs prescribed to women at visits to doctor’s offices and outpatient departments, followed by estrogens and progestins, antiarthritics, and medicines for acid/peptic disorders, in the Journal of Women’s Health.

By 2005, the CDC recently reported, antidepressants were the most prescribed drugs in the US during visits to doctors and hospitals and were prescribed far more often than even medications used to treat high blood pressure, cholesterol, diabetes, and headaches.

Yet, a recent analysis of studies on the efficacy of 12 second-generation antidepressants including SSRIs and serotonin and norepinephrine reuptake inhibitors (SNRIs), released on January 25, 2007, by the Agency for Healthcare Research and Quality’s (AHRQ), a division of the US Department of Health and Human Services, offers little support for the wide-spread use of these medications.

The AHRQ reviewed efficacy in treating major depressive disorder, dysthymia and subsyndromal depression (including minor depression), and also evaluated comparative efficacy for maintaining remission and for treating accompanying symptoms such as anxiety or insomnia or neurovegetative symptoms.

The review included 187 studies deemed to be of good or fair quality, including 89 head-to-head randomized controlled trials, 57 placebo-controlled randomized studies, with 126 of the studies sponsored by drug companies and 17 funded by government agencies or independent sources, and analyzed the effectiveness of Cymbalta, Wellbutrin, Effexor, Celexa, Lexapro, Prozac, Luvox, Remeron, Serzone, Paxil, Zoloft, and Desyrel, many of which are now also sold in generic form.

Overall the analysis found that in controlled studies, during 6 to 12 weeks of treatment, well over a third of the patients, or 38%, saw no improvement in their condition and 54% had only partial improvement and did not achieve remission.

In light of this clear lack of efficacy, it should be noted that as early as August 2004, the FDA label for SSRIs warned that “anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric”

According to one of the world’s leading experts on SSRIs, Dr Peter Breggin, author of The Antidepressant Fact Book, “few physicians realize that meta-analyses have shown that antidepressants work no better than placebo at lifting depression.”

So in the case of pregnant women he says, “The risk/benefit ration weighs a placebo effect against increased parental suicide and violence, and babies with congenital defects, babies undergoing withdrawal reactions, and babies whose brains have been forever changed by being soaked in SSRIs during their development.”

Dr Breggin also notes that the NEMJ researchers failed to consider the serious withdrawal reaction in newborns and the potentially disastrous consequences of SSRI use by pregnant women. “Withdrawal reactions confirm that the brain of the fetus has been bathed in SSRIs and that it has suffered significant functional changes,” he warns.

“It should be no surprise that it is not good to bath the growing brain in toxic drugs like SSRIs,” he says, “because serotonin is intimately involved in the development of the brain in utero and SSRIs inhibit normal brain cell development.”

Experts say, SSRI use creates an unnecessary risk for fetus. Dr David Healy, another leading authority on SSRIs, and the author of “The Creation of Psychopharmacology,” and “The Antidepressant Era,” says, “the overwhelming majority of women who are prescribed SSRIs are at little or no risk for suicide or other adverse outcomes from their nervous state.”

He points out that every pregnant woman may have symptoms of depression such as anxiety, disturbed sleep, fatigue, or a loss of interest in sex. “But having depressive symptoms and being depressed are two different things,” he states.

Dr Healy also notes the lack of efficacy shown with SSRIs, and says the risks of the neonatal withdrawal syndrome and serious birth defects to the infant far outweigh any benefits of their use by expectant mothers.

Houston Attorney, Robert S Kwok, is outraged by the new campaign to promote the use of SSRI with pregnant women. “It’s ludicrous to think a woman is at greater risk of depression during her pregnancy and should take antidepressants despite the proven risk to her developing fetus,” he states, “yet physician “opinion leaders” with industry ties are actively trying to convince doctors and patients of just that.”

Mr Kwok represents the family of Gavin Shore, a baby born with a severe cardiac defect known as Shone’s Anomaly after his mother was prescribed the SSRI Celexa during pregnancy and says Gavin’s mother was not warned that taking an SSRI could double the risk of her baby being born with a severe heart defect.

Although some of the reports citing the NEMJ studies in media mentioned that Glaxo money was involved in funding the CDC study, most neglected to mention the financial contributions of the other drug companies for the study, or the steady stream of drug money that flows to the medical facilities and researchers involved in the studies.

When combined, the named universities, hospitals and researchers involved have received money from Lilly, Pfizer, Wyeth, Glaxo, Aventis, Sanofi Pasteur, and the 3 companies that make generic versions of SSRIs.

The CDC study lists Harvard Medical School and Massachusetts General Hospital as participating and the Harvard Medical School receives nearly 25% of its funding from non-government sources, including nearly $3.5 million from Aventis Pharmaceuticals, $2.5 million from Bristol-Myers Squibb, and $2.1 million from Merck, according to an April 12, 2006 report in The Phoenix.

In addition, The Phoenix noted, SEC filings showed Harvard stock holdings of $16 million with Merck, $8 million of Bristol Myers Squibb, $34 million of Johnson & Johnson, and $33 million of Pfizer.

In one NEJM study, Dr Jan Friedman reported receiving honoraria for consulting from I3 Research, which is actually a huge conglomerate of “research” firms with names that begin with i3. The April 12, 2006 Phoenix reported that a firm called i3 Innovus, which co-authored 16 medical-journal articles in 2005, “provides integrated scientific strategies and solutions throughout the pharmaceutical product lifecycle.”

The Phoenix also noted that this i3 firm had a Boston office for its vice-president of US operations, Milton Weinstein, who also happened to be a professor at Harvard Medical School and Harvard School of Public Health.

The same group of industry backed research institutions credited in the NEJM CDC study, began the disinformation campaign to boost the sale of SSRIs to pregnant women more than a year ago when “experts” at Harvard and Mass General published a study to intentionally dilute the finding of a mounting number of studies that found serious birth defects to be associated with the use of the drugs by pregnant women.

In response to a study in the February 2006, New England Journal of Medicine that showed infants exposed to SSRIs in the womb were 6 times more likely to be born with the life-threatening lung disorder, persistent pulmonary hypertension, a study appeared in the Journal of the American Medical Association the same month warning that stopping SSRIs could greatly increase the risk of pregnant women relapsing into depression.

On February 1, 2006, the Associated Press described the methods used by the Massachusetts gang when conducting the JAMA study and said researchers “followed 201 pregnant women with histories of major depression who were taking drugs such as Prozac, Zoloft, Effexor and Paxil.”

“Because of ethical concerns,” the article said, “the researchers did not randomly assign the women to either stop or continue medication.”

Instead, the AP reported, the women decided what to do and then the “researchers watched what happened.”

But the actual report on the study shows that of the 201 participants, 13 miscarried, 5 terminated their pregnancy, 12 were lost to follow-up prior to the end of pregnancy, and 8 chose to withdraw from the study.

So when reporting on the few pregnant women that remained, the study said mothers were 5 times more likely to suffer a relapse than those who continued taking the drugs.

However, a highly relevant finding rarely mentioned, in what turned out to be this wee little study, is that 26% of the women who remained on the drugs became depressed anyways.

The study authors noted that of the 82 women who continued antidepressant treatment throughout pregnancy, 21 or 26% relapsed. But there were only 65 women in the group that discontinued the drugs, so the results logically showed a higher rate of relapse when 45 became depressed.

Moreover, nearly 2 years before the study was published in JAMA, on January 13, 2004, the lead author, Dr Lee Cohen was quoted in the New York Times as saying about 75 to 80% of pregnant women who go off antidepressants will relapse during the pregnancy.

Six months after JAMA ran the study, the July 11, 2006 Wall Street Journal explained why the 13 “experts” might encourage pregnant women to keep taking SSRIs, in stating the lead author, Dr Cohen, who was a Harvard Medical School professor and director of the research program at Massachusetts General, was a longtime consultant to the 3 antidepressant makers, a paid speaker for 7, and his research work was funded by 4 drug companies.

In fact, the Journal reported, “the study and resulting television and newspaper reports of the research failed to note that most of the 13 authors are paid as consultants or lecturers by the makers of antidepressants,” and “the authors failed to disclose more than 60 different financial relationships with drug companies.”

And just like clock-work, the Cohen’s study was widely cited in other journals promoting the sale of SSRIs to pregnant women. “In summary, it seems clear that the risks of not receiving adequate antidepressant treatment thus far outweigh the risks of adverse events, not only in infants but in mothers as well,” wrote Dr Pierre Blier of the University of Ottawa in editorial in the Journal of Psychiatry and Neuroscience, 2006;31(4):226-8.

“The population,” he warned, “should therefore learn to fear the illness more than the antidepressant.”

But as it turns out, Dr Blier conflicting interests included among others, being a consultant with Lilly, Forest Labs, Janssen, Wyeth and Sanofi-Aventis, and a contract employee with Forest Labs. He was also in the speaker’s bureau for Lilly, Forest Labs, and Wyeth, and received grant funding from Lilly, Forest Labs and Wyeth.

The JAMA study, along with a brief note from Dr Cohen himself, was also featured in the Spring 2006 issue of Massachusetts General Hospital’s Center for Women’s Health Newsletter, in a publication that downplayed the risk of just about all the birth defects discovered in recent years including heart birth defects and the infant withdrawal syndrome.

Since 1990, JAMA has required authors of studies to list all financial interests and has published the disclosures. In an online editorial in July 2006, JAMA editor, Dr Catherine DeAngelis announced her intention to enforce the policy in part by publicizing any author’s failure to follow the rules and specifically noted that 3 consecutive nondisclosures involved authors from Harvard Medical School and included Dr Cohen’s study.

On July 11, 2006, citing material promoting the events, the Wall Street Journal reported that the Massachusetts General psychiatry academy planned to conduct Continuing Medical Education seminars in a dozen cities across the US, with Dr Cohen overseeing a segment on the treatment of pregnant women with psychiatric disorders.

One of the funding sources for the seminars was revealed less than a year later on May 1, 2007, when the Journal reported the major recipients of the $11.8 million that Eli Lilly gave out during the first three months of 2007, and said the largest single grant “was $825,000 to Massachusetts General Hospital’s psychiatry department for a year-long educational program with more than 150,000 registrants.”

It should be noted that Lilly introduced the first SSRI, Prozac, in the late 1980s and its current best-selling antidepressant Cymbalta earned the company $1.3 billion in 2006.

The financial ties between the researchers and SSRI makers was brought to the attention of the JAMA editor by Dr Adam Urato and a letter from Dr Urato was also published in JAMA, stating that being the study dealt in part with the question of stopping antidepressants during pregnancy, the readers should be aware of the potential for pro-drug bias.

However, all that being said, the Cohen study is still being cited to promote the use of SSRIs with pregnant women, and as recently as April 26, 2007, in a paper by Dr Claudio Soares, director of Women’s Health Concerns Clinic, McMaster University, Ontario in Journal Watch Women’s Health, a publication put out by the NEJM.

“Results of a recent prospective study of pregnant women,” he wrote, “who were taking antidepressants at or near the time of conception demonstrated that women who opted to discontinue treatment during pregnancy were five times more likely to relapse than were those who stayed on treatment.”

“Despite the cautionary remarks commonly made by most regulatory agencies and medical societies about the use of psychotropic medications during pregnancy,” Dr Soares states, “considerable data supporting the efficacy and reproductive safety of antidepressants have accrued.”

“Conversely,” he warns, “evidence suggests that untreated depression has negative consequences for both mother and child.”

“In summary,” Dr Soares states, “clinicians should bear in mind the mounting evidence about the adverse effects of uncontrolled depression during pregnancy.”

But here too, Dr Urato, wrote a response to this obvious sales pitch objecting to the total lack of citations to studies that support the assertion that the risks of birth defects associated with SSRI are rare and that the benefits of SSRIs use to avoid relapse into depression outweigh the risks.

But most concerning, Dr Urato wrote, “is the complete lack of financial disclosure information to go along with the article.”

“As I was reading this piece,” he wrote, “I kept thinking to myself “‘Boy, this sounds like it was written by someone working for the antidepressant makers.'”

And sure enough, Dr Urato found that Dr Soares is on the Speaker’s Bureau for Forest Labs, Wyeth, Glaxo, and Pfizer and has received honoraria as a research consultant for Sepracor, Glaxo, Wyeth, and Neurocrine.

Mr Kwok is also highly critical of the increasingly common practice of using “opinion leaders” like Dr Soares to sell SSRIs to pregnant women, but states, “there will come a time when the drug manufacturers will have to face the music on SSRIs causing PPHN, and that time is coming soon.”

He says his firm has an abundance of new cases that prove it’s no coincidence that pregnant mothers on SSRIs have an increased likelihood of giving birth to babies with PPHN in families where there is no history of respiratory illness.

“Just yesterday,” Mr Kwok states, “I spoke to a mother who birthed a baby with a serious breathing disorder that requires regular use of a nebulizer, a device used to administer medication via liquid mist to the airways, commonly used in treating asthma and other respiratory diseases.”

“This young mother is now at risk of losing her job,” Mr Kwok reports, “since her infant requires full time care.”

He says doctors should be instructed to screen patients who are pregnant or planning to become pregnant and inform them of the risks of SSRIs to a developing fetus. “At least educate this “class” of women,” he says, “so they may make informed personal decisions.”

“Sure, the loss of this “class” may cost the drug manufacturers some profit,” he notes, “but it’s the right thing to do and it will save many families a lifetime of torture caring for a sick child like we see over and over again.”

The need to recapture pregnant women as customers is crucial for some SSRI makers. For instance, Forest Labs reported that Lexapro and Celexa accounted for 68% of the firm’s total sales for the year ending March 31, 2006, in its Annual Report filed with the SEC.

Back in May 2005, researchers from the University of Pittsburgh estimated that in any given year at least 80,000 pregnant women in US are prescribed SSRIs, in JAMA.

(This article is written as part of a series on Celexa related litigation and is sponsored by Robert Kwok & Associates, LLP)

Filed under: 2007, Birth Defects, Breggin, CDC, DTC, KOL, Kwok, SSRIs

More Adverse Effects Linked to SSRI Celexa

Evelyn Pringle November 14, 2006

According to testimony at an inquest into the deaths of Roxanne Richardson, 30, and her children, Luke, 3, and Grace, 20 months, an autopsy revealed that at the time of their murders, husband and father-turned-killer, Michael Richardson, had Celexa in his system higher than prescribed which may have caused him to become agitated and irritable.

When he arrived at the Richardson home on July 12, 2004, Detective Sergeant Fox said the four bodies lay side by side on a bed. The medical evidence was that Mrs Richardson had been stabbed in the chest and then suffocated, the children had been suffocated, and Mr Richardson had died from a gunshot wound, according to the November 1, 2006 Sidney Morning Herald.

A far cry from alleviating his depression, on the day of the tragedy, while pumped full of Celexa, Mr Richardson wrote in his diary: “I’m hurting so much, nothing matters to me any more except my family and they are getting taken away from me.”

Over the past 15 years, there have been a growing number of criminal cases where people have claimed that their aggression and violence was caused by the use of antidepressants like Celexa, a class of drugs known as selective serotonin reuptake inhibitors (SSRIs).

Psychiatrist, Dr Peter Breggin, author of 20 books including, “Toxic Psychiatry,” has been researching psychiatric drugs and serving as an expert witness and consultant in civil and criminal cases involving drug companies for more than 25 years.

In 1972, he founded The International Center for the Study of Psychiatry and Psychology (ICSPP), a non-profit research and educational network, focused on the impact of mental health theory and practices upon patient well-being, personal freedom, and family and community values. He also founded the journal, Ethical Human Sciences and Services.

According to Dr Breggin, all SSRIs can produce stimulation or activation with the potential for increased agitation, disinhibition, irritability, aggression, hostility, mania, and crashing into depression and suicide.

“They can also cause a flattening of emotional responses,” he notes, “including a loss of caring, that can unleash dangerous actions.”

“Beginning with the widespread use of Prozac in the early 1990s,” he says, “the struggle to gain public and professional recognition of antidepressant-induced suicide and violence has a long and stormy history. “

The debate peaked in 1994 when Dr Breggin testified against Eli Lilly in a case of Prozac-induced suicide and mass murder by a postal worker in Kentucky.

“My testimony, in effect,” Dr Beggin recalls, “was that the perpetrator, Joseph Wesbecker, hadn’t gone “postal,” he’d gone “Prozacal.”

After the drug company won a split jury decision at the end of the trial, the judge figured out that the trial had been fixed. “The plaintiffs,” Dr Breggin says, “had been paid off by the drug company to conduct a fake trial that was rigged to end in favor of the drug company.”

In the end, when the judge realized what happened, he was outraged and voided the verdict.

According to Dr Breggin, while the FDA and antidepressant makers continue to deny that SSRIs cause violence, many lives continue to come to tragic ends.

It wasn’t until late 2004, that the FDA finally made drug companies add a black box warning to the labels of SSRIs about the increased risk of suicide among patients taking the drugs, even though Dr John Abramson MD, author of, “Overdosed America,” and a clinical instructor at Harvard Medical School, says the FDA knew about the increased suicide risk since before the drugs were approved.

The findings from a study published in the Archives of General Psychiatry in 2000, he says, evaluating the findings from the “pivotal studies” submitted to the FDA on the 7 new antidepressants approved between 1987 and 1997, including Prozac, Zoloft, Paxil, Effexor, Serzone, Remeron, and Wellbutrin SR, went largely ignored.

In studies that included depressed but not suicidal patients, the completed suicide rate for those taking one of the new antidepressants was 842 in 100,000 per year, or 0.84%, while the rate of suicide for patients taking a placebo was less than half at 360 in 100,000, or 0.36%.

“In other words,” Dr Abramson explains, “the pre-approval studies considered by the FDA to be highest quality and most important for these 7 new and supposedly safer and more effective antidepressants showed that treating 1000 depressed non-suicidal patients for one year with the new drugs led to about 5 more successful suicides than if the same group of 1000 patients had been treated with a sugar pill.”

“This is an enormously high death rate,” he points out.

And although the incidence of violent behavior is not included in the above report on antidepressants, Dr Abramson says, “it certainly seems logical that when the risk of violent actions against self are more than doubled, that the incidence of violent actions against others might be similarly affected.”

At the very least, he notes, this possibility should have been studied.

Critics say, getting the FDA to issue warnings about the increased suicide risk with SSRIs was like pulling teeth. According to investigative journalist and author of, “Psyched Out: How Psychiatry Sells Mental Illness and Pushes Pills That Kill,” Kelly Patricia O’Meara, “based on the evidence that twice as many children in clinical trials showed a greater risk of suicidality taking the antidepressants, coupled with the evidence that the antidepressants in the majority of the clinical trials were no more effective than sugar pills, the FDA had little choice but to “request” the pharmaceutical companies add the black-box warnings.”

Also in 2004, what would become a steady stream of studies showing harm to infants born to mothers taking SSRIs began to emerge.

In February 2004, the study, “Maternal Selective Serotonin Reuptake Inhibitor,” by Philip Zeskind PhD and Laura Stephens, in the journal Pediatrics, reported that “first-trimester use of SSRIs has been associated with higher rates minor physical anomalies and miscarriages, thus suggesting possible early effects of SSRI exposure on embryonic development.”

The study also reported that third-trimester use off SSRIs had been associated with lower gestational age, low birth weight, higher rates of neonatal intensive care unit admissions.

In June 2004, a French study published in the journal Prescrire International, reported that newborns exposed to SSRI during pregnancy showed signs of agitation, altered muscle tone, and breathing and suction problems.

The following month, in July 2004, the FDA changed the labeling for all SSRIs, warning that some newborns exposed to SSRIs had developed problems requiring respiratory support, tube feeding and prolonged hospitalizations.

But as it turns out, the FDA had received hundreds of reports of adverse effects in infants born to mothers taking SSRIs over the past decade, according to WebMd. The most common adverse events reported included irritability, trouble eating, body rigidity, and respiratory problems, said Kathleen Phelan, a safety evaluator in the division of drug risk evaluation, to WebMD.

A February 2005 study in the journal, Lancet, screened the World Health Organization’s database on SSRI adverse reactions in cases of neonatal convulsions and withdrawal syndrome, and found that by November 2003, there was a total of 93 case reports of maternal SSRI use in babies born with convulsions or withdrawal syndrome.

An analysis of the reports showed 64 cases were associated with Paxil, 14 with Prozac, 9 with Zoloft, and 7 were associated with Celexa.

Research released earlier this year linked SSRI use by mothers during pregnancy to infants born with the life-threatening persistent pulmonary hypertension (PPHN) lung disorder. According to a study by researchers at the University of California, San Diego School of Medicine, in collaboration with Boston University’s Slone Epidemiology Center, in the February 9, 2006 New England Journal of Medicine, babies born to women who took SSRIs in the second half of pregnancy, had a 6 times greater risk of developing the lung disorder.

In September 2005, studies conducted by Danish and US researcher determined that SSRI use in the first trimester of pregnancy was linked to a 40% increased risk of birth defects such as cleft palate and that cardiac defects in newborns also appeared to be 60% more likely with women who used SSRIs.

In February 2006, a study conducted in Israel found that one out of 3 infants exposed to SSRIs in the womb showed signs of drug withdrawal at birth, including high-pitched crying, tremors, and a disturbed sleep pattern.

On April 7, 2006, the BBC reported a Canadian study of almost 5,000 pregnant women that found mothers on SSRIs were twice as likely to have a premature birth and also nearly twice as likely to have low birth weight infants and stillbirths.

Less than 3 months later, in July 2006, the FDA issued an advisory that warned against taking SSRIs together with triptans, drugs used to treat migraine headaches, because a life-threatening condition called serotonin syndrome may occur. The condition, the FDA said, causes serious changes in how the brain, muscles and digestive system work due to high levels of serotonin in the body.

Last month, doctors at the Cornell Medical Center, in New York, who were treating the two men for infertility, including one who was on Celexa, found that when the men stopped taking the SSRIs, their fertility problems disappeared, only to resume again when they went back on SSRIs.

The problem is believed to be caused by an adverse effect of SSRIs on both the concentration and swimming ability of sperm. The men were tested over a 2-year period

Dr Peter Schlegel, who presented the research at the American Society for Reproductive Medicine conference, in New Orleans, explained that:

“The patients had normal sperm counts and motility before medication. On the medication they have severe deterioration of both. The same patients going on and off medication had the same pattern. It shows a strong association.”

Impotence and delayed ejaculation are well-known side-effects of SSRIs, and now Dr Schlegel says he believes that the drugs may be preventing sperm from getting into semen.

“These were men with normal sperm counts that went to nearly zero when they were on these antidepressants but returned to normal when they were off them. It’s a dramatic effect and it’s never been described before,” said Professor Schelgel in the Guardian on October 24, 2006.

“We believe that while it’s had a profound effect on these two men,” he said, “it could be having a significant but more subtle effect on many more men.”

But no matter how many adverse events are found to be associated with SSRIs, there seems to be no way to curtail the over-selling of these drugs to all populations. For the year ending March 31, 2006, Forest Laboratories top selling drugs were the SSRIs, Celexa and Lexapro, which when combined, accounted for 68% of the drug maker’s sales.

However, there may be a few dents in the company’s profit margin for SSRIs in the coming years because according to Forest Lab’s Annual Report filed with the SEC on June 14, 2006, the company is a named defendant in approximately 25 active product liability lawsuits, with most alleging that Celexa or Lexapro caused or contributed to persons committing or attempting suicide.

In addition, Forest Labs may not know it yet, but the company will soon be hit with the first Celexa-related birth defect lawsuit alleging that the company engaged in “repeated and persistent fraud” by misrepresenting, concealing and otherwise failing to disclose, information concerning the safety and effectiveness of Celexa in treating pregnant women.

Named plaintiffs in the case will be Lacee Shore, who was prescribed Celexa during her first trimester of pregnancy and her baby Gavin Shore, who was born with heart birth defects. Attorney, Robert Kwok, of the Houston, Texas lawfirm Robert Kwok & Associates, LLP, is handling the case.

To cover lawsuits, according to Forest’s Annual Report, the company maintains $140 million of product liability insurance coverage per “occurrence” and in the aggregate.

However, in conclusion the Report points out that, “litigation is subject to many factors which are difficult to predict and there can be no assurance that we will not incur material costs in the resolution of these matters.”

Filed under: 2006, Birth Defects, Celexa, Forest, Kwok, sex, SSRIs, suicide

FDA Runs Protection Racket For Big Pharma

January 7, 2007 Evelyn Pringle

Why would Americans trust the FDA to regulate the pharmaceutical industry? Since the Bush administration took office the FDA has become the industry’s partner in crime.

The most notorious protection scheme put in place by the FDA and Big Pharma is the preemption policy that bans private lawsuits against drug companies in state courts once a drug and its label have been approved by the FDA.

On January 18, 2006, the FDA issued new rules for the labeling of prescription drugs, and in the preamble to the rules on page 43, the FDA says, State law actions “threaten FDA’s statutorily prescribed role as the expert Federal agency responsible for evaluating and regulating drugs,” requiring lay persons to second-guess its expert assessments of a drug’s risks and benefits.

So, after all of the concerns raised about the FDA’s failure to protect consumers against dangerous products over the last several year, by top experts from all over the world, the FDA has hereby declared itself the sole authority on decisions regarding prescription drugs, including whether a drug’s label contains adequate descriptions of indications for use, risks and benefits.

In an October 6, 2006, articled titled, “The Doctrine of Preemption,” Stan Kaufman aptly refers to the new policy as the “Doctrine of Preemptive Crony Capitalism.” When announcing this multi-billion dollar immunization gift to Big Pharma, the FDA told drug makers:

“We think that if your company complies with the FDA processes, if you bring forward the benefits and risks of your drug, and let your information be judged through a process with highly trained scientists, you should not be second-guessed by state courts that don’t have the same scientific knowledge.”

A statement saying the complete opposite was made in 1996, by the FDA’s Chief Counsel in a speech that said the FDA had a “longstanding presumption against preemption” and that “FDA’s view is that FDA product approval and state tort liability usually operate independently, each providing a significant, yet distinct, layer of consumer protection.”[

The preemption claim reverses a long-standing policy of permitting State actions intended to protect consumers and undermines the States’ ability to protect their citizens, yet State and local entities were given no opportunity to object to it.

Under Executive Order 13132, issued first by President Reagan, and then reissued by President Clinton, the FDA is supposed to consult with State and local authorities about the effects of each regulation it issues that affects the States.

Nowhere in the proposed rule did the FDA provide notice or seek comment on the preemption provisions added to the preamble. In the only proposed rule known to State and local officials, the FDA said that the regulation would not preempt State law. In fact, the language published in the Federal Register on December 22, 2000, explicitly stated that “this proposed rule does not preempt state law.”

The rule requested comment on products liability issues, but only by asking whether the new “Highlights” section raised liability concerns and, if so, how the FDA might alleviate those concerns without eliminating the Highlights section. This request can hardly be called “notice” of the preemption statement that suddenly appeared in the preamble in 2006.

By relying on this false representation, State and local authorities were robbed of any opportunity to object to the preamble. In a January 2006, letter to Michael Leavitt, Secretary of Health and Human Services, the National Conference of State Legislators called the regulation a “thinly veiled attempt on the part of FDA to confer upon itself authority it does not have by statute.”

The NCSL also stated the failure to allow for an appropriate comment period constitutes “an abuse of agency process and complete disregard for dual system of government.”

Ken Suggs, president of the Association of Trial Lawyers of America, was quoted in the January 19, 2006 Washington Post, as saying, the “fact that the drug industry can get the FDA to rewrite the rules so that CEOs can escape accountability for putting dangerous and deadly drugs on the market is the scariest example yet of how much control these big corporations have over the political process.”

Legal experts point out that it was never the intent of Congress to preempt private lawsuits in State courts, and that in fact, when Congress was considering the Food, Drug, and Cosmetic Act of 1938, it specifically rejected a proposal to include a private right of action for damages on the ground that such a right already existed under State common law.

According to Houston attorney, Robert Kwok, who handles complex pharmaceutical litigation involving drugs such Fosamax, Norvasc and SSRI antidepressants like Celexa:

“The real losers from this attempted power grab would be the millions of Americans who depend on safe drugs. Without the protection of state laws Big Pharma can ride shipshod over Americans who are injured by their unsafe drugs. That’s unacceptable and I’m seeing even conservative judges resist it.”

Many members of Congress have also weighed in on the issue and reaffirmed that Congress never intended to preempt State claims in a February 23, 2006, letter to Michael Leavitt, Secretary of Health and Human Services, from Representatives Henry Waxman (D-Calif.), John Dingell (D-Mi.), and Sherrod Brown (D-Ohio).

Rep. Maurice Hinchey (R-NY) and Senator Edward Kennedy (D-MA), have threatened to fight preemption through legislation if necessary. Rep. Hinchey issued a press release on January 18, 2006, immediately after the policy was announced, stating that the “FDA has once again gone to bat for the drug industry by fully endorsing a policy that shelters pharmaceutical companies from Americans who want to file lawsuits because a drug has made them or a loved one seriously ill, or in some cases caused death.”

Rep. Hinchey also called it “the latest example of the FDA sticking its nose where it does not belong and treating the drug companies as clients rather than regulated entities.”

The FDA’s language on page 38 of the preamble that states “whether it be in the old or new format, the Food, Drug and Cosmetic Act preempts conflicting or contrary state law,” appears to imply that the preemption policy is retroactive.

Part of the language also says that lawsuits against doctors are preempted for failure-to-warn patients of risks associated with a drug, apparently even when a drug is prescribed “off-label,” for a use other than those approved by the FDA.

“Pre-emption would include not only claims against manufacturers,” the FDA states, “but also against health-care practitioners for claims related to dissemination of risk information to patients beyond what is included in the labeling.”

The FDA has never before, in its entire history, claimed that a drug label preempts actions against health care professionals for failure-to-warn patients about risks. In fact, labels carry no information about the risks or benefits of “off-label” uses.

Critics see this language as an attempt to immunize all the doctors who the industry has convinced to over-prescribe drugs to treat conditions or patient populations for which the drugs have never been approved as safe and effective to increase profits.

“Doctors need to be held just as accountable as the drug manufacturers when things go wrong,” attorney Kwok says.

“The profession of medicine is in danger of being totally co-oped by the business of medicine,” he warns, “with more and more of the burden is being placed on the consumer.”

“And with only minimum consumer protection standards set by the FDA, that isn’t very reassuring,” Mr Kwok notes.

“I predict there could be a flood of litigation,” he says, “before FDA policy changes any more.”

In any event, restrictions that the FDA places on drug labeling do not prohibit drug companies from disseminating warnings about a danger by other means. When it originally promulgated these regulations, the FDA made clear that:

These labeling requirements do not prohibit a manufacturer, packer, re-labeler, or
distributor from warning health care professionals whenever possibly harmful adverse effects associated with the use of the drug are discovered. The addition to labeling and advertising of additional warnings, as well as contraindications, adverse reactions, and precautions regarding the drug, or the issuance of letters directed to health care professionals (e.g., “Dear Doctor” letters containing such information) is not prohibited by these regulations. 44 Fed. Reg. 37434, 37447 (June 26, 1979).

One of the main authors of the new labeling rules was the FDA’s Chief Counsel at the time, Daniel Troy, who in previous employment fought the FDA in court to allow drug companies to promote drugs to doctors for “off label” use.

Its now obvious when looking back, that Mr. Troy was appointed by the Bush administration to implement tort reform under the guise of preemption, and under the cover of the Office of Chief Counsel at the FDA.

In the midst of the Vioxx and SSRI antidepressant disasters, instead of going after the drug makers for knowingly injuring hundreds of thousands of consumers with dangerous products, Mr. Troy devoted the majority of his time on the clock to filing five amicus briefs on behalf of Big Pharma to be used against the very citizens who were paying his salary.

In his briefs, Mr. Troy focused his main attention on protecting the profits of the makers of SSRIs, drugs second only to Vioxx when it comes to the concealment of studies and information about harm that if revealed, could have prevented tens of thousands of deaths and injuries over the past 20 years.

And even though there has been an infinite number of reports over the past decade regarding an increased risk of suicide with SSRIs, instead of withdrawing the approval of the drugs, requiring more studies, or demanding a warning be added to their label, Mr. Troy did nothing to protect potential SSRI victims as Chief Counsel of the FDA.

In late 2004, Mr. Troy quit the FDA to go back into private practice to once again represent pharmaceutical companies openly against private citizens, only with the added benefit of using the preemption defense he put in place.

On October 9, 2006, Mr. Troy published an article in the Legal Times, that said, “I was also at the FDA while January’s Physician Labeling Rule, which contains a statement in its preamble about the FDA’s pre-emption authority, was written.”

“And I now,” he states in an obvious ad for new clients, “advise and represent companies confronting state-law claims that implicate the pre-emptive effect of FDA requirements.”

In the Times article, Mr. Troy points out the importance of drug companies staying cozy with the FDA to ensure success in future litigation. “Savvy companies,” he wrote, “are recognizing that how they interact with the FDA today may profoundly affect their pre-emption defenses in the future.”

“They are trying to ensure their communications with the agency are as formal as they can be,” he said, “in light of commercial considerations and the need to stay on the FDA’s good side.”

“More formal communications,” he advises, “can help buttress a future case for why a particular state law claim should be pre-empted.”

In the article, Mr. Troy brags that his filing of FDA briefs on behalf of Big Pharma “has reduced the negative consequences of the current pharmaceutical-liability regime.”

But for once, he at least mentions that it cost the tax payers plenty. “FDA involvement in state-law cases is not an ideal solution,” he writes, “not least because each instance of such involvement involves the costly investment of substantial agency resources.”

It should be noted that two years before Mr. Troy filed his first brief as a kick-off for the preemption policy, the “costly investment of substantial agency resources” went for an FDA brief, in which the FDA acknowledged “the historic primacy of state regulation of matters of health and safety” and the appropriateness of a presumption against preemption where the state-law claims allege defective design, negligent manufacturing, or failure-to-warn in, Buckman v. Plaintiffs’ Legal Committee, 531 US 341 (2001).

In the Legal Times, Mr. Troy goes on to explain that the new labeling rule is intended to limit the direct involvement of the FDA in lawsuits. “The preamble to that rule,” he says, “makes an official statement of FDA’s views on preemption easily available to courts hearing state-law tort cases.”

“If courts give appropriate deference to this statement of FDA’s considered judgment,” he notes, “FDA will not be forced to file briefs in individual cases.”

Until reading this article, its likely that most people had never realized that Mr. Troy was “forced” to file briefs on behalf of Big Pharma while he worked at the FDA.

In a March 31, 2006 paper, titled, State-Level Protection for Good-Faith Pharmaceutical Manufacturers, Mr. Troy can be found advising State lawmakers to pass shield laws for Big Pharma based on a Michigan model, to “help to reduce the negative consequences of the current pharmaceutical-liability regime,” he says.

“In so doing,” he states, “they would help to encourage the development of new drugs, preserve the availability of existing drugs, reduce upward pressure on drug prices, and assure rational prescribing.”

Such a statement might be a wee bit credible if it also included a suggestion for the lowering of the multi-million dollar annual salary and benefit packages enjoyed by Big Pharma CEOs or a reduction in the billions of dollars that are spent each year on illegal off-label promotion and marketing schemes.

For all the whining he does about litigation keeping products off the market, Mr. Troy cannot cite a single case in which a failure-to-warn claim interfered with the FDA’s federal regulatory authority or kept a drug off the market. In fact, in a lecture to Big Pharma attorneys in December 2003, on how to use the preemption defense, Mr. Troy told the attorneys that the FDA had “no good evidence” showing product liability concerns “keep good products off the market,” even though he had “combed the literature” to find such evidence.

Apparently to help resolve this nagging little problem, Mr. Troy told the defense attorneys to pay for research to find some evidence to back this claim even if it was weak, stating: “you guys really shoot yourself in the foot by not funding research to this effect. … I’ll even take anecdotal evidence and stories if you have them.”

Mr. Troy filed the FDA’s first brief in support of Big Pharma in September 2002, in the California Zoloft case titled Motus v. Pfizer, after he was contacted by Pfizer attorney, Malcolm Wheeler, in the summer of 2002, requesting that he get the government involved to help Pfizer win the preemption argument.

Despite the fact that Pfizer had paid Mr. Troy’s law firm over $358,000 in the year before he became Chief Counsel, Mr. Troy argued later that he did not become involved in the case until after the 1-year grace period in which employees may not participate in activities involving former clients. From all public accounts, the time period elapsed less then a month before he entered the case.

In the brief, Mr. Troy argued that any warning that suggested a link between Zoloft and suicidality would have been false and misleading, and the FDA would have rejected any effort to add such a warning. However, that argument contradicts 21 CFR § 314.126(b), which requires warnings to be added based on reasonable evidence of an association, even absent proof of a causal relationship. The preemption issue was never decided in Motus because the case was concluded on unrelated grounds.

Legal experts say the preemption defense will not only be used in SSRI-related suicide cases, it will be applied in SSRI cases involving the failure-to-warn about other types of injuries and deaths caused by these drugs as well.

For instance, Big Pharma will no doubt attempt to preempt cases filed on behalf of infants born with birth defects to mothers who unwittingly took the drugs during pregnancy, such as with Lacee Shore, who was prescribed Celexa during her first trimester of pregnancy and as a result, her baby, Gavin Shore, was born with serious heart birth defects and diagnosed with Shone’s Complex, which can lead to the obstruction of blood flowing to the body from the left side of the heart.

Gavin has already gone through several surgeries in attempt to correct the heart defects and will have to undergo more in the future.

The successful use of the preemption argument in a case such as this, where the drug maker, Forest Laboratories, could and should have warned doctors and pregnant women about the possibility of birth defects associated with Celexa, would leave the Shore family strapped with the burden of life-long medical costs related to Gavin’s condition.

According to attorney Kwok, who is handling the Shore case, the birth defect situation is even more devastating than with patients harmed by Vioxx because the Celexa victims are so young. “Their whole lives,” he says, “if they survive, will be under the threat of illness and additional surgery, with a very poor prognosis.”

Mr. Kwok points to a 1990 study conducted at the University of Michigan that shows the outlook for infants born with heart defects like Gavin is very poor. “One quarter of patients die after their second operation,” he says.

“The second operations are very often necessary,” he explains, “because of the complexity of the heart problem.”

Forest Labs knew about the potential for birth defects caused by Celexa because more than two years before Gavin was born, on June 9, 2004, Web MD reported that the FDA was concerned about reports that SSRIs may cause adverse effects to babies born to mothers taking the drugs late in pregnancy.

According to Web MD, the FDA had been receiving reports for 10 years. In fact, it said that hundreds of reports on adverse effects in babies were received involving all the SSRIs sold in the US, which would include Prozac, Paxil, Luvox, Zoloft, and Celexa.

In July 2004, the FDA finally asked the SSRI makers to change the labels, warning that some infants had developed problems requiring tube feeding, respiratory support, and prolonged hospitalizations.

On September 1, 2005, the BBC reported that Danish and U.S. scientists found that cardiac birth defects appeared to be 60% more likely in newborns when women used SSRIs.

Studies show that women are prescribed SSRIs twice as often as men and yet the drug makers have made no effort to evaluate the use of these drugs with pregnant women. And as a result, Mr. Kwok says, “new moms are finding out too late that the Celexa they took was putting their unborn baby in grave danger.”

A successful preemption ruling would go a long way as far as protecting profits against damage awards based birth defects, because pregnant women represent a major share of the market. According to a May 2005, study in the Journal of American Medical Association, 80,000 pregnant women are prescribed SSRIs in any given year in the U.S., which means there are bound to be many cases where babies were born with birth defects.

The majority of courts that have addressed the preemption argument have ruled against it. One of the first federal courts to specifically rule against the FDA’s preamble position was a Nebraska District Court on May 31, 2006, in Jackson v. Pfizer, where the plaintiffs’ son took both Zoloft and Effexor and then committed suicide.

The parents alleged that the drugs caused their son to commit suicide and Nebraska law required additional warnings about the suicide risk. The drug maker defendants moved for summary judgment claiming that the State law claims were preempted by the FDA.

The court said that the claims were not preempted because the federal regulations did not conflict with State law and specifically held that there was no Congressional directive that the field was preempted.

The court stated the FDA preamble was not persuasive and pointed out that the Eighth Circuit had adopted the proposition that the FDA prescribes only minimum standards and the Fourth Circuit had declared that complying with federal regulations does not release a manufacturer from liability.

The court also noted that the FDA “failed . . . to allow the states an opportunity to participate in the proceedings prior to a preemption decision,” and dismissed the FDA’s brief stating that it “will not treat amicus briefs as the force of law.”

On May 25, 2006, a federal court in Pennsylvania was the first to grant the FDA’s preemption rule full deference in a wrongful death and survival action, with failure-to-warn claims against Paxil maker GlaxoSmithKline, and generic Paxil maker Apotex, in Colacicco v. Apotex, Inc, Civ No 05-cv-5500, 2006 WL 1443357 (E.D. Pa. May 26, 2006).

In this case, the plaintiff alleged that his wife’s suicide resulted from the drug makers’ failure-to-warn of the increased risk of suicide linked to Paxil and its generic equivalent.

The judge on his own initiative, invited the FDA to file a brief. The current Chief Counsel, Sheldon Bradshaw, went to bat for the drug makers and filed a brief at record speed within 20 days, urging the court to dismiss the lawsuit on the basis of preemption, stating that in October 2003, when Paxil was prescribed to the suicide victim, “there was no reasonable evidence available at the time of an association between adult use of the drug and suicide.”

The FDA argued that any such warning regarding an association between Paxil and suicide would have been false or misleading, and thus would have constituted misbranding under the FDCA.

The plaintiff responded by arguing that the court should not afford deference to the brief because 21 C.F.R. § 314.70, does permit manufacturers to strengthen labels without FDA approval and the FDA has no authority to simply declare that a drug is misbranded.

The court disagreed and determined that it was to give significant deference to the amicus brief based on the U.S. Supreme Court’s decisions in Chevron, Medtronic, and Geier which state that an amicus brief is an appropriate form to express preemptive intent and held that the principles of deference do not permit a court to question the FDA’s interpretation of its own regulations.

The plaintiff argued that the preamble which was promulgated in 2006 could not be retroactively applied to the October 2003, death of his wife. However, the Court said that preemption could be applied retroactively because the preamble simply clarified the FDA’s “longstanding views on preemption,” and characterized the preamble as an “interpretive rule,” rendering retroactivity concerns “irrelevant.”

The Court went on to say that even if the preamble did not apply retroactively, it would have found preemption anyway based on the views previously expressed in amicus briefs by the FDA.

An appeal is pending on the Colacicco decision, and the case has drawn amicus support from a dozen scientists and doctors who contend that preemption “would threaten the public health and eliminate an important counterpart to the public health objectives of the FDA.”

The national non-profit consumer advocacy organization, Public Citizen, the Trial Lawyers for Public Justice, a national public interest law firm, and the Association of Trial Lawyers of America, an international coalition of attorneys, law professors, paralegals, and law students, have together filed an amicus brief supporting Mr Colacicco, stating:

“Products liability lawsuits help to protect patients from drugs with undisclosed risks because the potential for being held liable for harm caused by their products provides a powerful incentive for drug companies to make their products as safe and effective as possible and to revise labels as soon as new risks become apparent.

“Furthermore, because FDA lacks authority to subpoena documents from the companies it regulates, products liability lawsuits help to uncover information that can lead to safer products.”

In fact, the group points out, since at least several months before the victim’s suicide, the FDA had been reviewing data about a possible link between SSRIs and suicidality, and the agency issued a Public Health Advisory on the topic in October 2003, the same month that Mrs. Colacicco died.

The amicus brief also notes that the FDA’s preemption statement lacks the “consistency” needed to warrant any degree of deference because prior to 2002, the FDA’s consistent view was that State common law was not preempted by federal drug regulation. “For example,” the brief wrote, “in both 1979 and 1998, in preambles accompanying various drug regulations, FDA stated that state tort law did not interfere with federal regulation.”

In 1998, when addressing pharmacists’ provision of written patient information for “Medication Guides,” when issuing the final rule, the FDA rejected calls for the agency to express an intent to preempt State regulation of labeling requirements stating:

“FDA regulations establish minimal standards necessary, but were not intended to preclude states from imposing additional labeling requirements. States may authorize additional labeling but they cannot reduce, alter, or eliminate FDA-required labeling.” 63 Fed. Reg. at 66384.

According to the amicus brief, “The authority to regulate drug labeling may carry with it the authority to address state drug labeling regulations, but it does not carry with it authority to determine the preemptive effect of federal regulation on state common-law compensation systems.”

It appears that the FDA’s own regulations acknowledge that preambles are not statements of law and that they should not be presented as such in legal proceedings.

The amicus group states that the preamble is not part of the regulation, will not appear in the Code of Federal Regulations, and does not have the force of law. “In fact,” the brief notes citing FDA regulations, “a longstanding FDA regulation provides that a statement in a regulatory preamble constitutes only an “advisory opinion.”

The FDA recognizes that an advisory opinion may be used to “illustrate acceptable . . . procedures or standard, but not as a legal requirement,” the brief points out.

“Having made no effort to legislate on the topic of drug-related damages remedies,” the brief concludes, “Congress can hardly be said to have authorized FDA to supersede the damages remedies traditionally provided by the states.”

There was an extremely important preemption ruling handed down on June 9, 2006, in the Vioxx case of Doherty v. Merck prior to the beginning of the actual jury trial. Merck moved to dismiss the failure-to-warn claim arguing that the preamble barred claims with respect to FDA approved drugs.

The June 9, ruling from the bench, drew massive attention to the case when New Jersey Superior Court Judge, Carol Higbee, refused to exclude the claims.

“The preamble, as I see it, is a political statement by the FDA,” she said.

“The primary purpose of it,” she stated, “is to criticize state courts and to set forth the FDA’s position, not to criticize state courts so much as to set forth the FDA’s position that they believe there should be federal preemption of all tort actions.”

“What the preamble is saying,” Judge Higbee noted, “is the FDA should be the final word.”

She refused to dismiss the claims based on the preamble she said, because it “has nothing to do with science.” In conclusion, she told Merck defense attorneys:

“It has nothing to do with what happened back in 2000, 2001, 2002, when these issues were being debated. It is contrary to the U.S. Supreme Court’s decisions. It is contrary to all the law on preemption.

“And I am not going to allow you to use it.”

Merck later enjoyed a victory at trial when a jury decided that Vioxx was not the main cause of Elaine Doherty’s heart attack, but a favorable ruling on the preemption issue prior to trial could have potentially saved the company billions of dollars. According to the company’s SEC filings, as of October 9, 2006, Merck is a named defendant in about 13,850 Vioxx cases in the New Jersey State court coordinated litigation.

The next victory using the preemption argument was a major win in August, 2006, when a California court dismissed the Celebrex failure-to-warn claims against Pfizer, In re Bextra and Celebrex Marketing Sales Practices and Product Liability Litigation, No M: 05-1699 CRB, 2006 WL 2374742 (N.D. CA, August 16, 2006).

In opposing the motion, the plaintiffs argued that because the FDCA does not provide a monetary remedy, Congress must not have intended the FDA to have authority over damage claims and that the FDA’s position on preemption was not entitled to deference because it was clearly erroneous and inconsistent with the regulations.

Saying the FDA specifically considered the safety risks about Celebrex alleged in the lawsuit and determined the risks should not be included on the label, the court said the failure-to-warn claims “conflict with the FDA’s determination of the proper warning and pose an obstacle to the full accomplishment of the objectives of the FDCA.”

But the judge refused to dismiss the false advertising claims. The plaintiffs argued that the Celebrex ads were false and misleading because they exceeded the labeled and approved gastrointestinal benefits and also minimized the established risks of the drug.

Pfizer claimed that because it submitted the ads for FDA approval, and the FDA did not object, the FDA had determined that the ads were accurate and struck a fair balance of the risks and the benefits of Celebrex.

However, the court refused to preempt the claims without a record showing that the FDA had reviewed each ad and approved it. The court also pointed out the FDA’s silence about whether its regulations preempt false advertising claims, in contrast to its stated position on failure-to-warn claims.

A little over a month later, on September 29, 2006, across the country in New Jersey, the court in McNellis v. Pfizer, refused to allow the preemption defense based in part on the fact that the text of FDA regulations had remained unchanged for years, and the regulations did not conflict with New Jersey’s failure-to-warn laws.

The McNellis Zoloft-suicide case comes with a history. On December 29, 2005, the U.S. District Court for the District of New Jersey had also denied Pfizer’s original motion for summary judgment. The court reasoned that the FDA’s approval of a label creates only a minimum standard and that the drug maker may strengthen the warnings as long as the new warning is not false or misleading.

After the FDA published the new rule and preamble with the preemptive language in January 2006, Pfizer filed another motion asking the court to vacate the order denying summary judgment, or to certify the question for interlocutory appeal

In opposing the motion, Ms. McNellis said that the preamble amounted to nothing more than the FDA’s opinion on preemption; the same opinion expressed previously by the FDA in amicus briefs, and the same opinion already rejected by the court. It is irrelevant that this opinion now comes in the form of a preamble to a regulation rather than an amicus brief, she said.

In her brief filed on March 2, 2006, Ms. McNellis argued that the FDA had also exceeded its authority, stating:

“In this instance, an executive agency, the FDA, has expressed an opinion that Congress has never agreed to. Without notice or comment, the FDA found it within its jurisdiction to go against the wishes of Congress as well as the wishes of those states which have product liability failure-to-warn statutes.”

Ms. McNellis also pointed out that the last six courts to decide the issue “have found, consistent with this Court’s finding, that the FDA regulations establish minimum requirements such that they do not preempt state tort laws.”

She also noted that the preamble was not in effect at the time that her father committed suicide as a result of taking Zoloft.

The court held that regulations allow a drug company to increase warnings when new risks emerge, that the Food, Drug and Cosmetic Act does not contain a preemption clause, and that Congress gave no implicit empowerment to the FDA to preempt State law.

Following the McNellis decision, on October 16, 2006, a federal court in Pennsylvania refused to grant the drug maker’s preemption motion on the failure-to-warn claims in Perry v. Novartis Pharma Corp, — F Supp 2d —-, 2006 WL 2979388.

This case involved Elidel, a drug used to treat eczema, prescribed to Andreas Perry when he was 2-years-old. Six months after he began using the cream, in October, 2003, Andreas was diagnosed with a form of cancer known as lymphoblastic lymphoma.

Elidel belongs to a class of drugs known as calcineurin inhibitors, so called because they reduce immune activity by inhibiting the activity of the enzyme calcineurin. Prior to the approval of Elidel for treating skin conditions in children over 2 years of age, calcineurin inhibitors were used as systemic immunosuppressants in organ transplant patients.

Systemic use of the drugs has long been known to increase the risk of cancer and the labels on the drugs prescribed to organ transplant patients say so. But because Elidel is applied topically for eczema, it was not known at the time of approval in December 2001, whether long-term use posed a risk of cancer.

This case illustrates why drug companies must be made to alert the public of known dangers as soon as they are known. On February 15, 2005, an FDA advisory committee met to discuss calcineurin inhibitors. In particular, reports of “off label” use of the drugs in children under two caused concern for some members of the committee.

At the meeting, the committee voted to add a “Black Box” warning about the possible increased risk of cancer associated with the topical use of Elidel, and the lack of long-term safety data on the use of the drug.

On March 10, 2005, the FDA told the drug maker to add a “Black Box” warning and issued a public health advisory about the possible cancer risk. However, it was nearly a year later when Novartis finally got around to adding a “Black Box” warning to Elidel’s label on January 19, 2006.

In their brief in opposition to the preemption motion to dismiss, the plaintiffs said that the FDA’s broad claim of preemption is not entitled to deference, “whether it is expressed in the January 2006 Preamble to the Final Rule,” or “in amicus curiae briefs filed by the agency in support of drug manufacturers.”

“The FDA’s claims,” the brief wrote, “which are tantamount to an advisory opinion, lack the force of law and contradict the FDA’s governing statute, its regulations, and its regulatory purpose.”

It also noted that the FDA’s current opinion directly opposes the FDA’s longstanding views on preemption. “For these reasons,” the brief pointed out, “a majority of courts that have considered this issue, both before and after the FDA issued the Preamble, have held that FDA approval of labeling does not preempt state failure-to-warn claims.”

In denying Novartis’ preemption motion, U.S. District Court Judge, Stewart Dalzell, of the Eastern District of Pennsylvania, wrote in the decision that the FDA’s new “Preamble is not entitled to any special consideration in our analysis.”

Where the agency attempts to “supply, on Congress’s behalf, the clear legislative statement of intent required to overcome the presumption against preemption,” no deference is warranted, he noted.

In reaching its decision, the court said preemption would only apply if a specific warning about Elidel and pediatric cancer had been considered by the FDA and found to be unnecessary and that had not happened in this case.

In discussing the FDA’s assertions in its amicus brief, the court stated, “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 wrote, “the persuasive force of the argument diminishes.”

The court also said that even if the Preamble represents a change of policy with the force of law, it would not apply to this case. “The FDA cannot retroactively absolve Novartis of a duty it may have owed the Perrys in 2003,” it wrote.

The court also noted that the FDCA provides no remedy for an injured consumer and said, “a finding of preemption here will foreclose a remedy that was traditionally available and for which federal law provides no substitute.”

In its decision, the court made an interesting observation about the viability of the preemption defense on failure-to-warn claims based on other available methods of warning the public about the dangers of a drug, stating:

“It is worth noting that, even where FDA regulations or other federal law prevent a manufacturer from modifying the approved labeling, a modification of the label is not the only form that a warning could take.

“If, for example, a plaintiff claimed that a manufacturer was negligent in not sending a letter to prescribing physicians or other health care professionals, that might present a different case, even if modification of the approved labeling were prohibited.”

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,” and further stated:

“If, at some future date, Congress determines that FDA monitoring is sufficiently effective on its own to warrant the elimination of state law incentives for manufacturers to provide adequate warnings, it also has the authority to declare that failure-to-warn suits, like the Perrys’ action, are preempted.”

“Until it does so, however,” the court said, “in the absence of a specific FDA safety determination, such suits can go forward.”

(This article is written as part of a series on pharmaceutical litigation and is sponsored by Robert Kwok & Associated, LLP)

Filed under: 2007, Bextra, Birth Defects, Bush, Celexa, Colacicco, Elidel, FDA, Glaxo, Kwok, McNellis, Novartis, Paxil, Perry, Preemption, SSRIs, Troy, Vioxx

FDA Feeling The Heat

January 19, 2007 Evelyn Pringle

Over the past year, the Bush administration’s FDA has been the focus of non-stop investigations and with the Democrats in control of Congress, a long overdue overhaul of the agency is in the cards.

The Government Accountability Office has identified serious problems within the FDA. In an April 21, 2006, report, the GAO found the FDA’s performance “disorganized,” “bureaucratic,” and undermined by infighting between drug evaluation administrators whose allegiance is with the pharmaceutical industry, and the Office of Drug Safety.

According to the GAO, the drug safety office is under-funded, lacks independence and lacks decision-making responsibility. It also criticized the way FDA scientists were prevented from speaking at advisory committee meetings on drugs they were studying.

Investigators point to a major conflict within the Office of New Drugs because it is not only responsible for approving a drug in the first place, it is also responsible for taking regulatory action related to the safety of drugs once they are on the market.

The GAO report said that day-to-day oversight of safety issues is still hampered by poor information, lack of legal authority to order drug company studies, and bickering between the powerful FDA bureau that reviews drugs for approval and a smaller safety office.

To improve postmarketing safety, the GAO recommends that Congress expand the FDA’s authority to require drug companies to conduct studies when additional data is needed.

Another report was released on June 26, 2006, titled, “Prescription for Harm: The Decline in FDA Enforcement Activity,” after an investigation was commissioned by the House Committee on Government Reform to evaluate the FDA’s enforcement activities related to the pharmaceutical industry under the Bush administration.

When requesting the investigation, Rep. Waxman, wrote to the committee Chairman specifically asking for “attention to cases where career investigators believed official action to protect the public health was warranted but could not proceed.”

For the investigation, in addition to reviewing the FDA documents, the investigators obtained information from current and former FDA officials and independent experts.

The experts consulted included Dr. Jerry Avorn, Professor of Medicine at Harvard Medical School; Dr. Michael Wilkes, Vice Dean of Medical Education at the University of California at Davis School of Medicine; and Sammie Young, former Director of Compliance at FDA’s Bureau of Biologics and a 29-year veteran of the agency.

As to methods available for enforcement, when a serious violation of FDA standards is found during an inspection, the FDA has the statutory authority to seize or recall products, impose civil fines, or initiate criminal action.

However, most often the FDA will send the manufacturer either a “warning letter” or a “notice of violation,” which is also called an “untitled letter.” A warning letter notifies a company of violations, requires a written response, and warns that failure to correct the violations can lead to additional enforcement action.

Under FDA procedures, the agency must evaluate the response to a warning letter to determine whether the violations have been corrected. If the firm’s response is inadequate, the agency must take other enforcement action “as necessary to achieve correction.”

An untitled letter is less serious and informs a company of the violations but does not require a written response or warn that enforcement action may follow if violations are not corrected. An untitled letter also does not require an FDA follow-up.

The Prescription for Harm investigation found that there has been a sharp decline in FDA enforcement actions against pharmaceutical companies since December 2001. After reviewing the records, in a May 25, 2006, letter, Dr. Avorn told the Reform Committee, “In all of FDA’s once-proud recent history, I cannot recall a time of greater concern about its work on the part of doctors, patients, and policy researchers.”

“In overview,” he said, “there appears to have been a sharp drop-off in the number of warning letters FDA has issued in recent years, from an average well over 1,000 for the period 1992 – 2001 to an average of only about 700 for the years 2002 – 2004.”

“It is unlikely,” Dr Avorn advised, “that the behavior of the regulated industries improved so much during these years to account for a reduction of 300 warning letters per year.”

Another expert consulted for the investigation, Dr. Wilkes, stated in a June 10, 2006, letter to Rep. Waxman:

“Today the snake oil salesman need not travel in horse and cart nor even in automobiles — they use the internet and the mail to make the same outrageous claims with products that contain sometimes dangerous ingredients and often inert useless ingredients.

“And the Food and Drug Administration seems unable and unwilling to step in to protect the American public.”

The Report cites examples of serious problems that were ignored, including a GlaxoSmithKline plant in Puerto Rico, where the FDA’s field inspectors found several violations between 2002 and 2004, and even recommended that the facility be closed. Yet it was not until 2005, that the FDA censured Glaxo, and even then it did not impose a fine, shut down the plant, or order a recall of the products it was unable to seize.

In some cases, the Report states, FDA headquarters rejected the recommendations of field inspectors despite findings that violations led to multiple deaths or serious injuries. Internal agency documents obtained during the investigation reveal that in at least 138 cases over the last 5 years, the FDA failed to take actions recommended by field inspectors.

The problems identified by inspectors in these cases included 110 where drug labeling and new drug application requirements were violated; 99 cases where manufacturing standards were violated; and 2 cases where firms failed to report adverse drug events. And over 40% of the files, the report said, involved multiple types of violations.

In nearly half of the cases, the FDA took no enforcement action against the firm and in the remaining cases, it took action that was weaker than recommended by the field inspectors.

Most interesting is the fact that during the Congressional investigation, the FDA provided no records from the Office of Chief Counsel, even though a previous investigation had attributed a sudden decline in enforcement actions to the issuance of a change in FDA policy by then Chief Counsel, Mr Daniel Troy, in September 2001, that required all warning letters and untitled letters to be approved by his office before being issued.

According to the revised procedures, the Chief Counsel is required to “state in writing the reason for nonconcurrence” whenever it objects to an enforcement action. Yet when the FDA was asked to explain why there were no records from Mr. Troy’s office, FDA staff claimed that the Office of the Chief Counsel does not maintain copies of its decisions or recommendations, or even a record of which files it has reviewed.

The FDA was slammed again when the Institute of Medicine released a September 22, 2006, report that said that the nation’s drug safety system is impaired by “serious resource constraints that weaken the quality and quantity of the science that is brought to bear on drug safety; an organizational culture in [FDA] that is not optimally functional; and unclear and insufficient regulatory authorities particularly with respect to enforcement.”

The report listed the agency’s lack of stable leadership in recent years, and the detrimental effect on personnel; the failure to provide the agency with the necessary authority to regulate post-marketing assessments and enforce compliance; the undue influence caused by the agency’s dependence on user fees; and the impact of stacking advisory committees with members that have clear conflicts of interest.

A recent session of the Senate Committee on Health, Education, Labor, and Pensions, gave the Democrats the first opportunity to show how they intend to deal with the major problems at the FDA, so aptly identified by investigations over the past year.

A November 17, 2006, hearing was held to push forward Senate Bill 3807, the “Enhancing Drug Safe and Innovation Act of 2006,” previously introduced by outgoing chairman, Senator Michael Enzi (R-WY), and incoming chairman, Senator Edward Kennedy (D-MA), who began working on the bill shortly after the Vioxx disaster.

At the hearing, critics called for stricter conflict of interest rules for advisory panels. Merrill Goozner, Director of Integrity in Science Center for Science in the Public Interest, testified about the conflicts of interest involving the expert panel that reviewed the COX-2 inhibitors, and how the panel decided that Vioxx was safe enough to stay on the market, even though its maker, Merck, had already removed it from the market.

Mr. Goozner told the Senators that ten of the 32 scientists on the committee had financial ties to the drugs’ makers. “Had their votes been eliminated,” he said, “two of the drugs in the class would have been voted down by the panel.”

The president of Consumers Union, Jim Guest, testified that improvements are needed to prevent future disasters like Vioxx and called for a rule requiring that at least 90% of the members who decide whether a drug should be approved be free of conflicts of interest.

Dr. Steven Nissen, of the Cleveland Clinic, who has served on advisory panels, testified to “a crisis in public confidence in the FDA following an unprecedented series of revelations about drug and device safety” and called the Senate reform bill a “major step forward.”

“I served on a 2001 Advisory Panel that recommended a warning label for Vioxx,” he told the Senators, “but it took 14 months before the FDA could secure agreement from the company to accept a weakly written warning.”

Dr. Nissen also said improvements “in the Advisory Committee process will help to ensure that FDA consultants are less likely to be influenced by financial conflicts of interest.”

In 2005, a law was passed that required panel members to make full disclosure of all financial ties to Big Pharma. However, after reviewing the disclosure forms submitted, the FDA is still permitted to grant waivers that allow experts to sit on panels even if they have financial ties to a drug company.

On April 21, 2006, the Boston Globe discussed the practical effects of the law since it was enacted and quoted FDA critics as saying “the new transparency has changed little, and scientists who have conflicts of interest can still guide FDA decision making.”

In less than 6 months, the Globe determined, close to 100 waivers had been granted.

Congressman Hinchey is the author of an amendment to the spending bill that funds the FDA, which would ban waivers. “Plain and simple,” he says, “if a doctor or scientist has a personal, financial stake in a drug they should not be allowed to sit on an FDA advisory panel and determine whether that drug is safe.”

In response to the FDA’s renewed push to maintain its ability to grant waivers, on July 24, 2006, Rep Hinchey released a statement stating, “The FDA continues to demonstrate a lack of commitment to ensuring that all of its advisory panels are filled with members who have no conflicts of interest with the drug or device being reviewed.”

“Saying that there are not enough potential advisory panel members available without conflicts, as the FDA argues, is an empty claim,” he said.

Most disturbing, he said is that the FDA denies only 1% of the waivers requested. “When the FDA is handing out waivers 99 percent of the time,” he states, “it is a clear sign that the system is broken.”

No doubt in attempt subdue the hornet’s brought on by the investigations into the approval of Ketek based on fraudulent studies, in late July 2006, the FDA announced a series of changes it plans to make in the methods used to evaluate clinical trials.

One would require a company to notify the FDA immediately if it believes a researcher has committed fraud during a clinical trial. As it is now, drugs companies are trusted to remove unreliable data and are not required to report any fraudulent activity to the FDA until they actually submit the new drug application.

The agency also says it plans to clarify which adverse events must be reported to the review boards that monitor the studies and standardize the forms used to collect information and revise the rules on how patients may qualify to participate in clinical trials.

The new FDA commissioner was confirmed on December 7, 2006, but critics say the agency is incapable of change under the Bush regime. Rep. Hinchey released a statement stating: “Unfortunately, the Senate’s confirmation of Dr. Andrew von Eschenbach represents anything but a fresh start for one of the most troubled agencies in the federal government.”

“I have not seen anything substantive from Dr. von Eschenbach,” he stated, “to make me believe that the mismanagement, misplaced priorities, and ineptitude of the agency’s leadership will change during his tenure.”

“Among many other things,” he said, “Dr. von Eschenbach has presided over the FDA as it issued a new rule that prevents Americans from filing lawsuits against drug companies if they or a loved one become seriously ill or die as the result of a particular drug.”

“And in just the last few days,” Rep. Hinchey reported, “the FDA has approved numerous waivers for panelists on its advisory boards who have financial conflicts of interest with drugs and devices they are reviewing.”

Houston attorney, Robert Kwok, makes the point that “fortunately, there are just two years left in this administration, so Dr von Eschenbach’s term may be short.”

“But he can still do a lot of damage in that time,” he warns, “to the rights of Americans, their health, and their privacy.”

(This article is written as part of a series on pharmaceutical litigation and is sponsored by Robert Kwok & Associated, LLP)

Filed under: 2007, FDA, GAO, Glaxo, IOM, Ketek, Kwok, Troy

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