GlaxoSmithKline has paid out close to $1 billion to resolve lawsuits involving Paxil since the drug came on the market in1992, according to a December 14, 2009 Bloomberg report. But the billion dollars does not cover the more than 600 Paxil birth defect cases currently pending in multi-litigation in Pennsylvania.
Glaxo has settled about 10 birth defect cases, according to Sean Tracey, a Houston attorney who represented the family of a child victim in the first jury trial that decided in favor of the plaintiff on October 13, 2009, Bloomberg reports. The settlements in those lawsuits averaged about $4 million, people familiar with the cases told the new service.
First Trial A Bust for Glaxo
The first trial, in the case of Kilker v Glaxo, ended with a jury in Philadelphia finding that Glaxo "negligently failed to warn" the doctor treating Lyam Kilker's mother about Paxil's risks and the drug was a "factual cause" of Lyam's heart defects. The jury awarded the family $2.5 million in compensatory damages.
After the trial, juror Joe Mellon told Bloomberg that Glaxo did not conduct adequate studies on Paxil. "There were a couple of what I thought were safety signals and what the plaintiffs presented as safety signals that they should have maybe looked into further," he said.
On October 14, 2009, the American Lawyer reported that the plaintiff's lead attorney, Sean Tracey, had quizzed the jurors about what swayed their decision. "They said the fact that GSK never adequately studied their own drug was a big deal," Tracey said. "The animal testing they did showed that they had a potential problem, and they didn't follow up with adequate studies on animals or humans."
Glaxo's lead attorney in the Kilker trial was King & Spalding partner, Chilton Varner.
Over 600 Trials To Go
A number of birth defect cases are set for trial in 2010. Andy Vickery, who practices at the Houston firm of Vickery, Waldner and Mallia, is handling several cases, with the Novak trial set to start first. The case is unique in that it involves an infant born with heart birth defects to Derek and Laura Novak on April 4, 2002, after Laura was prescribed Paxil during pregnancy for the off-label treatment of migraine headaches.
"Although one might worry that this would cause a jury to blame the prescribing doctor," says Vickery, "in this case, we can show that GSK encouraged this use, by sending out over 1500 "medical information" letters touting the benefits of Paxil for migraine headaches, and by leaving "approved WLF reprint" articles with the prescribing doctors."
Delaney Novak underwent open heart surgery on April 29, 2002, and again on February 21, 2003. Cardiac catheterization procedures were performed on December 4, 2002 and May 25, 2006. She will likely need repeated heart surgeries as she continues to grow.
In December 2005, the FDA reclassified Paxil from a pregnancy Category C drug to a Category D. Category D means studies in pregnant women have demonstrated a risk to the fetus. An advisory to healthcare professionals specifically stated that the "FDA has determined that exposure to paroxetine in the first trimester of pregnancy may increase the risk for congenital malformations, particularly cardiac malformations," and advised:
"Despite this categorization," says Vickery, "in numerous lawsuits across the country, Glaxo has continued to deny that Paxil causes birth defects."
"Hopefully that issue has now been laid to rest by the jury verdict in Philadelphia," he notes.
Case of the Dead Rats
During opening statements in the first trial on September 15, 2009, Sean Tracey told the jury they were "going to see documents in this case that have never seen the light of day before."
"You will see internal GlaxoSmith documents that the FDA hasn't seen, that the United States Congress hasn't seen, and that no jury has ever laid their eyes on before," he said. "They have been under seal for over three years."
Many of the sealed documents related to the Paxil studies conducted on rats and rabbits. The world-renowned expert from the UK, Dr David Healy, testified on behalf of the plaintiffs.
Paxil was originally owned by a Danish company called Ferrosan, and that company did the preliminary animal studies on rats and rabbits to look at teratogenicity around 1979 and 1980.
Healy explained that a teratogen is an agent that will cause birth defects and "it could be a drug or maybe a virus or maybe an illness."
In addition to birth defects, he said, a teratogen can cause a fetus to be born dead or cause a miscarriage, which is death before birth.
The jury heard about studies 295, 296 and 297, with the most damning being study 295, in which three groups of pregnant rats were given Paxil at doses of 5, 15, and 50 milligrams. The pregnancy outcomes at birth, and 4 days beyond, were then compared to rats born to mothers who received no Paxil.
The rat pups born to mothers who did not receive Paxil were all born alive. Of the 415 pups born to mothers who were given Paxil, 47 were born dead.
In the group of rats exposed to 5 milligrams of Paxil, 65 percent were dead by day four. In the 15 milligram group, 92 percent had died by the fourth day. Of the pups exposed to 50 milligrams, 100 percent were dead by day 4.
Eighty-eight percent of the pups born to mothers who received no Paxil were still alive at day four.
Autopsies were not performed on all the rats to figure out why they died or whether they had birth defects, and specifically heart defects.
After Tracey described the study in his opening statement, in regard to the product information that Glaxo was providing in April 2005, during her opening statement, Glaxo attorney, Varner, told the jury, "GSK in its label reported on the animal studies, including the death of the rat pups that you have heard so much about this morning."
"I would like you to note three things about the discussion in the product information about the animal studies," she said.
"First, there were no birth defects in the study," she told he jury. "That is, there were no malformations or difficulties, structural difficulties, with the animals."
"Second," she said, "the rat pups who died shortly after birth were dosed at something like ten times the normal dose."
"And, third, the dosing occurred not in the first trimester, the dosing occurred in the third trimester and continued throughout lactation," Varner told the jury.
"You will hear expert testimony that the death of the rat pups is believed to have been due to a lactation problem," she said, "it was during the lactation period that these pups died."
While Healy was testifying, Tracey read part of a summary on the study that directly contradicted Varner's claims in stating: "Females were dosed for 14 days prior to pairing, throughout the pairing period, during gestation and for those females allowed to litter during lactation."
He then asked Healy whether the female rats were exposed to Paxil for more than just the third trimester. "Yes, they were," Healy said. "They were actually exposed throughout the pregnancy and for a period of time before the pregnancy and after."
He also told the jury that there were three major malformations in the Paxil exposed group, and "there may well have been more."
"The figures from the studies do give grounds for concern that there were, in fact more," he said, "far more."
The fact that the more Paxil they got the more they died, "indicates that the drug has played a part ... in whatever the cause of death is," Healy told the jury.
"It's clearly the drug that has caused the death," he said. "What we aren't clear from here is just what actually happened. Why they died."
In 1980, Glaxo had a doctor by the name of John Baldwin review the Ferrosan rat and rabbit studies. In a March 20, 1980 memo to the company, Baldwin discussed the studies and further dispelled Varner's claim that the rats received 10 times the normal dose.
"At first the examination of individual litter data, et cetera, supports the possibility of embryo lethality then this observation at nonmaternally toxic dose levels which are only three to six times the proposed human dose could contraindicate the use of Paroxetine in pregnancy," Baldwin wrote.
"That means that this appears to be grounds for concern from the work that Dr. Baldwin has reviewed," Healy told the jury.
"That Paxil is a drug that if it comes on the market, may cause birth defects," he said. "So that it would be classified with the drug like Accutane where the drug would have to come on the market contraindicated."
Which "would mean in this case," Healy said, "do not use the drug in women of childbearing years unless, for instance, they're using some form of birth control."
Another portion of Baldwin's memo stated: "On the other hand, if the embryonic death is unrelated to treatment, we would have to repeat the study at higher dose levels to produce some maternal or embryonic/fetal effect. There remains the possibility of this compound could be teratogenic at higher dose levels."
"This means that Dr. Baldwin is saying there is a real risk here from the data that we have that this drug may cause birth defects," Healy told the jury. "We need to do more work to actually before it's out, does the drug come with this risk or not."
"He says we need to check and see if the company that has made this drug has conducted this extra research or are in the process of doing the extra research or not," Healy said. "The implication being that if they haven't done it, we should."
In reviewing the documents for the case, Healy found nothing to show that Glaxo ever did the studies that Baldwin was talking about. "I know they did further studies, but I don't think they did anything to address the issues that were raised by 295, 296, 297," he said. "Or if they did, they kept it well hidden it would seem."
Yet nine years after he wrote the memo, Baldwin published a 1989 paper on the reproductive toxicology of Paxil in a journal called, "Active Psychiatric Scandinavia," and stated: "There appeared to be no selective effect on the embryo or any signs of teratogenicity."
Baldwin "appears to be saying here that there is no evidence that the drug causes birth defects," Healy told the jury. "That appears to me to be incompatible with the data that we reviewed earlier."
Baldwin's paper was published the same year the new drug application for Paxil was submitted to the FDA on November 10, 1989.
Incriminating Data Destroyed
During the trial, the jury saw an exhibit showing minutes from a teleconference for a Paxil project team meeting, at which Anne Bell and others were present, on March 26, 1998. Page eight of the minutes stated: "It has already been discovered that raw data from four of the original Ferrosan sponsored toxicology studies conducted at Huntingdon Life Sciences were destroyed by HLS in 1993."
Healy told the jury that he had done studies for Glaxo and other major pharmaceutical companies and he still had the raw data 15 or 20 years later. "From my work on the serotonin system back in the early '80s, almost 30 years ago," he said, "I still have the raw data."
"The idea that I would destroy the data is almost inconceivable," Healy stated.
People may be concerned about a particular study and want to go back and look at the books, he said. "It's a bit like auditing a major company like Enron."
But it's "even more important actually in science," Healy told the jury. "People with a different point of view need to be able to say, look, show me the data."
They may "even suspect that I didn't do the study," he said, "so a defense for me is to be able to say here are the notebooks, here are the clinical records."
So you have to "be prepared to have all sorts of challenges," he told the jury. "But for that to happen, the notebooks, the clinical records, the lab notebooks must be there."
Healy testified that he did not believe the raw data from the original four Ferrosan studies had ever been located. "I believe there were efforts to try and find the microfilms, but they have not been found," he said.
Healy explained that when studies are done, there are a set of procedures called "good laboratory practice," or GLP.
"And it is hoped these days when a company brings a drug to the market," he said, "that the animal work that they do and the human work they do will conform to good laboratory practice and good clinical practice."
"And part of the requirements here of good laboratory practice is that the raw data is maintained," he told the jury.
Later in Healy's testimony, Tracey showed the jury that Study 295 itself, in regard to raw data, under "maintenance of records," stated "this material will be stored," and the "material will not be discarded or released from these laboratories without the sponsor's prior consent."
Initially, Paxil was FDA approved in 1992, with a Category B rating for pregnant women, meaning animal studies failed to demonstrate a risk to the fetus.
During the trial, it came out that the FDA employee who signed off on a Category B rating, a Dr Evoniuk, went on to work for Glaxo in the marketing department that sells Paxil.
A former FDA scientist, Doctor Suzanne Parisian, also testified as an expert for the plaintiffs. Adam Peavy, of the Houston firm of Bailey, Perrin and Bailey, handled her testimony.
Parisian testified that Doctor Sparenborg, a toxicologist at the FDA, raised a concern that there might be a problem with Paxil being a teratogen in 1995, when the pregnancy rating was changed from Category B to Category C.
When the company applied for approval of Paxil to treat Panic Disorder, Sparenborg suggested that the company "do a cross-fostering study to see if the adverse effect is occurring before the baby is born or after the baby is born," she said.
"Cross-fostering is ... taking rats from treated mothers and putting them with a control rat that didn't receive the drug," she explained to the jury. "So you are looking at whether the effect in the rat that could be produced in the pup was due to the mother herself or if it was something that was due to the rat before it was born."
The FDA asked Glaxo to submit a protocol for the study, "for our concurrence," before initiating it. But to her knowledge, Parisian said, Glaxo never submitted a protocol and never conducted a cross-fostering study.
She testified that such a study "would have helped to address where the negative effects were coming from."
While Parisian was testifying, the jury was shown the label for Paxil as it appeared in early January 2005, when Lyam's mother was prescribed Paxil as a Category C drug, with a discussion about the death of rat pups that implied the pups only died if the mothers received Paxil during the last trimester.
The label stated: "in rats there was an increase of pup deaths during the first four-day lactation when dosing occurred during the last trimester."
Parisian told the jury that there were deaths in pups born to mothers exposed to Paxil in the first and second trimesters as well. This Paxil label "implies to a physician that the animal studies support that it is safe to give the drug to the woman in the first and second trimester; that you need to be concerned about it in the last trimester," she testified.
The label is saying "there is no evidence of teratogenic effects," she said, "that means that it's safe for the first trimester. "
"If a physician were to read this, they would be more likely to prescribe it early in pregnancy," she told the jury.