The Bitter Pill

The Official Blog of UNITE – uniteforlife.org

Paxil Birth Defect Litigation – First Trial A Bust For Glaxo

Evelyn Pringle February 18, 2010

GlaxoSmithKline has paid out close to $1 billion to resolve lawsuits involving Paxil since the drug came on the market in 1992, 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.

(The Paxil Birth Defect Litigation Update Series is sponsored by the Houston law firm of Vickery, Waldner and Mallia at http://www.justiceseekers.com)

Filed under: 2010, Birth Defects, ghostwritten, Glaxo, Kilker, KOL, Paxil, Paxil birth defect litigation, SSRIs, Vickery

Ghostbusting in Paxil Birth Defect Litigation

Evelyn Pringle March 1, 2010

A month before the first Paxil birth defect trial against GlaxoSmithKline was set to begin, the Associated Press ran the headline, “Glaxo Used Ghostwriting Program to Promote Paxil,” in reporting on a program called “CASPPER,” which allowed doctors to “take credit for medical journal articles mainly written by company consultants.”

“Drug companies frequently hire outside firms to draft a manuscript touting a company’s drug, retain a physician to sign off as the author and then find a publisher to unwittingly publish the work,” the Associated Press said on August 19, 2009. “Drug company salespeople often present medical journal articles to physicians as independent proof that their drugs are safe and effective.

Between 2000 and 2002, articles from the CASPPER program appeared in five medical journals. On August 21, 2009, Jim Edwards on BNET, described the CASSPER ghostwriting brochure. The document shows that the intent of CASSPER was to flood the market with ghostwritten information, he said. It stated: “Paxil Product Management has budgeted for 50 articles for 2000.”

The trial in Kilker v Glaxo ended on October 13, 2009, 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 family was award $2.5 million.

Ghostwriting 101

The world-renowned neuropsychopharmacologist from the UK, Dr David Healy, testified as an expert witness for the plaintiffs in the Kilker trial.

While testifying, Healy explained the process of ghostwriting to the jury. He said ghostwriting probably began seriously in the 1980s. “It’s where an article appears under the name of usually a fairly distinguished person in the field,” he testified.

But it involves more than just the true author being concealed, he told the jury. “It’s a process where the ghostwriters work for companies who are very good at getting articles into the best journals in the field, like the New England Journal of Medicine, and recruiting some of the best known names in the field to be the apparent authors of the articles.”

“They may come from one of the big named universities like Princeton or whoever, but the actual fact the person who appears to be the author isn’t the true author,” he said. “If you were to read the article, you often don’t get any hints of who the true author of the article actually was.”

Ghostwriting impacts doctors in the real world trying to make decisions on whether to prescribe a drug in several ways, Healy told the jury. For instance, he said, if he was doing his own writing, he “would write an article on the drug, warts and all.”

“But if the article has been written by a ghostwriter working for one of the pharmaceutical companies,” he said, “the chances are the warts are somehow going to vanish.”

“The article will talk about the good aspects of the drug and will leave out the risky issues which are probably the most important things for the practicing doctor to know,” he explained.

If the ghost author comes from an extremely distinguished university, doctors reading the article will think it has to be right, he said. “The simple fact that the article is going to be apparently written by this big named person and appears in an extremely good journal means that most average doctors will think this has to be true,” he told the jury.

It’s not just the case of the doctor who reads the article being deceived, he said. “It’s the fact that the credibility of the institution is and the name is being used to sell the drug, as well.“

Healy came face-to-face with ghostwriting when one of the drug companies offered to ghostwrite his articles, he said. Since then, he has researched the ghostwriting process to assess how common it is.

The assessment found that “at least half, maybe more, of the articles that appear in major journals under the names of the best known people in the field, are ghostwritten when they have to do with pharmaceutical drugs,” he told the jury.

“If they have to do with the drugs that are being sold at the moment, the ones that are fashionable at the moment, then these articles are highly likely to be ghostwritten even when they appear in the very best journals,” Healy said.

Ghostwriting Up Close

While testifying, Healy told the jury that he was familiar with companies that Glaxo hired to ghostwrite literature and put other doctors’ names on it. “I think the leading firm in the field was one called STI,” he said. “This stands for Scientific Therapeutics Information.”

The jury was shown a July 28, 2003, document sent to the Glaxo product manager for Paxil, by Sally Laden, working for STI, which stated: “Thank you for offering me the chance to work with you to write two review articles.”

“This letter summarizes my fees for this project,” Laden wrote. “The safety paper is priced higher because of a greater number of named authors and the anticipated additional work involved in assessing the CR data in progress.”

For the development of the manuscript, and up to five drafts, the price quoted was $12,000. One of the topics for a manuscript was on the safety of antidepressants in breast-feeding.

“The first draft will be the first run through the material,” Healy told the jury. “She will have put the article together laying out the issues, laying out the references, structuring the paper up in the way that the journal she actually expects that this paper is going to go to will want the article structured.”

Draft 2 goes back to Glaxo again and the author, whoever is actually going to put their name on the paper. Then draft 3 goes back to Glaxo and the author for sign-off, and then there will be a final version that goes to the journal, Healy explained. Then draft 5 is revisions from journal reviewers, he said.

He noted that Laden said the safety paper is more expensive because there was going to be more authors. “I should emphasize that more authors here does not mean more authors writing the paper,” Healy told the jury. “It means more names appearing on the authorship line.”

“She has to recruit people and the people whose names are on the authorship line get paid for being authors,” he explained.

Sally Laden’s “name has appeared on a range of different articles that have been produced for GlaxoSmithKline, not just on the issue of giving drugs to women of childbearing years but across the board,” Healy said.

During Healy’s testimony, the family’s lead attorney from Houston, Sean Tracey, introduced the actual manuscript by STI. “This is an article that is going to go to a journal,” Healy said. “It has been authored by Ms. Laden, contrary to what appears there.”

The names Zachary Stowe and Jeffrey Newport appeared on the authorship line. Healy noted that Draft 4 stated: “Final article cover page to be removed.”

“The cover page will be removed,” he explained, “because the journal will treat the article quite differently if they think that the true author is not on the authorship line.”

Healy said the paper was an example of ghostwriting. “It is going to go to a journal called Psychopharmacology Bulletin,” he testified. “And in this particular issue of the journal where this paper later comes out, every paper in that issue of the journal has to do with Paxil.”

The jury was then shown the actual article that was published and it was the exact same article but without Laden’s name on it.

Healy testified that Stowe runs the women’s mental health program at Emory University and publishes on SSRIs and women’s health issues, with publications favorable to Paxil, and also gives seminars and talks for other doctors which outline “how it can be a good thing to treat women of childbearing years with Paxil.”

He was not allowed to tell the jury how much Glaxo had paid Stowe over the last year or two, which was revealed by an investigation led by Iowa Senator, Charles Grassley, as the ranking Republican on the US Senate Finance Committee. The amount Stowe got paid “is not public knowledge where you can show me a document that says it,” the judge said.

However, Stowe’s Glaxo earnings are most certainly public knowledge. A google search in December 2009, with the following three key words in quotes, “Stowe” “GSK” “paid,” brought up 15,800 hits.

On June 10, 2009, in reference to Stowe, the Wall Street Journal reported, “Emory University has disciplined a prominent psychiatrist who was being paid by an antidepressant maker at the same time he was conducting federal research about the use of such drugs in pregnant women.”

The National Institute of Mental Health said “it is reviewing Stowe’s activities, prompted by a letter from a U.S. Senate committee that said Stowe received $253,700 in 2007 and 2008 for “essentially promotional talks” for the drug maker GlaxoSmithKline,” the June 11, 2009 Atlanta Journal-Constitution reported.

The charts with dates for Stowe’s promotional talks reveal that many times he gave two talks for Glaxo on the same date and made five grand per day, in addition to payment for all traveling expenses. On one date, he billed $96 for meals alone.

For ready reference, the list of academics in the field of psychiatry identified by Grassley’s investigation thus far, as not fully disclosing money from drug companies, includes Joseph Biederman, Thomas Spencer and Timothy Wilens at Harvard, Charles Nemeroff and Zackery Stowe from Emory; Melissa DelBello at the University of Cincinnati; Alan Schatzberg, president of the American Psychiatric Association, from Stanford; Martin Keller at Brown University; Karen Wagner and A John Rush from the University of Texas; and Fred Goodwin, the former host of the radio show, “Infinite Minds,” broadcast for years by National Pubic Radio, before it was thrown off the air.

The supplement to the Spring 2003, “Psychopharmacology Bulletin,” found online, sure enough shows the ghostwritten paper, “Clinical Management of Perinatal Depression: Focus on Paroxetine,” with the names Stowe and Newport, along with papers by Martin Kelly, Charles Nemeroff, Alan Schatzberg, Karen Wagner, and Kim Yonkers, for a total of fourteen Paxil papers altogether.

Under “Disclosure,” the article ghostwritten by Laden stated: “This work was supported by an unrestricted educational grant from GlaxoSmithKline. Doctor Stowe serves as scientific advisor for and receives research grants from Pfizer and GlaxoSmithKline. He also receives grant support from Wyeth.”

The disclosure that the work was supported with a grant from Glaxo would not tell a doctor reading the paper that it was actually written by somebody else, Healy said.

While testifying, Healy explained that an “unrestricted educational grant, if I were to receive one, it would assume that I am saying things that are relatively favorable to the pharmaceutical company who has given me the educational grant.”

“If I am saying things hostile to the drug,” he said, “I will not get an unrestricted educational grant, although the word “unrestricted” suggests that I should.”

Stowe’s undisclosed income above was from Glaxo alone. In August 2007, he was listed as an author on a study titled, “Atypical Antipsychotic Administration During Late Pregnancy,” in the American Journal of Psychiatry.

According to the disclosure section, Stowe has received research support from Glaxo, Pfizer, and Wyeth, has served on advisory boards for Glaxo, Wyeth, and Bristol-Myers Squibb, and has served on speaker’s bureaus and/or received honoraria from Glaxo, Lilly, Pfizer, and Wyeth.

The second author on the ghostwritten paper, Jeffrey Newport, is the associate director of Emory’s Women’s Program. Newport was also an author on the “Atypical Antipsychotic” study. He has received research support from Glaxo, Lilly, Janssen, the National Alliance for Research on Schizophrenia and Depression, NIH, and Wyeth, and, he has served on speaker’s bureaus for Glaxo, AstraZeneca, Lilly, Pfizer, and Wyeth, according to the disclosures.

The next person the jury heard about was Charles Nemeroff. He was also an author on the atypical study. Nemeroff was the Chief of Psychiatry at Emory, until he lost the position last year, Healy told the jury. “He’s possibly best known or was the best known psychiatrist in the United States.”

“He influenced an awful lot of heads of departments, professors of psychiatry, general people within the field of academic mental health, and through them and an awful lot of prescribing doctors here in the U.S. And, indeed, perhaps worldwide,” Healy testified.

A link to “Articles” on the Emory website in mid-2009, brought up roughly 90 studies and papers that include the co-author Nemeroff.

Healy said he believed Nemeroff was one of the founding members of the Paxil advisory board and he participated in continuing medical education seminars with talks on Paxil.

Nemeroff would have been “the key person in producing the kinds of talks with slides that would have been held for large audiences of doctors, and then those slides and talks would have been distributed out to different doctors in the field who hadn’t been at the major meetings as he gave his talk,” Healy told the jury.

During his testimony, Tracey showed Healy a document from a continuing medical education seminar titled, “Fertility, Mood and Motherhood,” and Healy said the material for the seminar was prepared by Glaxo for Nemeroff. It was again supported by unrestricted educational grant from Glaxo and Nemeroff “was reimbursed for his role in this,” Healy pointed out.

Healy was also not allowed to testify about Nemeroff’s fall from grace at Emory, how much he was paid by Glaxo, or his failure to disclose over a million dollars from drug companies.

Dr Bernard Carroll, a past chairman of the department of psychiatry at Duke University Medical Center, summarized the Nemeroff saga well on the Healthcare Renewal website on November 3, 2008, in writing: “The fallout to date includes his severance from several NIH-funded projects at Emory University School of Medicine, a freeze of NIH funding for a major center grant, and his stepping down from Emory’s chair of psychiatry while an internal investigation proceeds.”

During her cross examination of Healy, Glaxo’s lead attorney, Chilton Varner, presented an exhibit showing a continuing medical education presentation given by Nemeroff.

“Can you see that in this continuing medical education program Doctor Nemeroff says that paroxetine, sertraline, fluvoxamine, (are) not associated with increased risk of teratogenicity or other complications?” she asked Healy.

“Yes, I do,” he replied.

In small print, the disclosure for the presentation showed Nemeroff had received research grants and participated in the speakers bureau and consulted for Glaxo, Eli Lilly, Solvay and Pfizer.

During re-direct, Tracey asked Healy to tell the jury what the actual results of the study that Nemeroff was discussing in the presentation showed, and specifically when Paxil was looked at alone. The results “showed that there was a 1.8-fold increase in the odds ratio of a birth defects to the women who have been taking Paxil during pregnancy,” Healy testified.

“Overall, for this group of drugs there was an increase in risk,” he said, “but specifically for Paxil the risk was greatly increased.”

“And beyond that,” Healy stated, “what isn’t included here in the conclusions, overall there was a — on this group of drugs, there was a doubling of the rate of miscarriages on the drug compared with the rate of miscarriage for the women who are being compared who weren’t on the drug.”

“There was also an increased rate of women going on to voluntarily abortions on the drug,” he added.

One of the lead authors on the study was Gideon Koren. “Doctor, without giving any details,” Tracey asked Healy, “do you know whether Doctor Koren has ties to the pharmaceutical industry?”

“I know he has,” Healy said.

During his opening statement, Tracey told the jury that 1998 was a big year for Paxil because a study came out by a doctor named Gideon Koren, and a researcher named Kulin, that looked at Paxil and two other SSRIs.

The study compared women who took SSRIs, to women who didn’t take any SSRIs, and the number of birth defects in the two groups was the same. “So Doctor Koren concluded that SSRIs appear to be safe,” Tracey said.

“Within, literally within 24 hours,” he told the jury, “GSK’s marketing machine cranked up and they faxed this information to their entire sales force.”

And the sales force took this information and began to use it to sell to women, he noted. “What they didn’t tell anybody was this,” Tracey said. “That when you separated Paxil out from the other SSRIs, you saw that Paxil was causing birth defects, that there was an increased risk of birth defects in this study in these women when you looked at Paxil by itself.”

“That was not in the paper,” he said. “That information was not found out until two years ago.”

While testifying, Healy was barred from telling the jury about Koren’s involvement in one the biggest academic research scandals in history a few years back when he sent vicious anonymous letters to discredit fellow researchers and denied doing so until DNA evidence from postage stamps proved he was lying years later. In September 2003, the Canadian Association of University Teachers reported on the disciplining of Koren in the CAUT Bulletin as follows:

“The Ontario College of Physicians and Surgeons has formally reprimanded University of Toronto professor of medicine Dr. Gideon Koren. He had written anonymous harassing letters about Dr. Nancy Olivieri and three colleagues during Olivieri’s dispute with the Hospital for Sick Children, the University of Toronto and Apotex Inc. He then had lied repeatedly to conceal his responsibility. The college also cited him for additional misconduct, in research.”

The Teachers Association further explained in the Bulletin: “The college’s finding of research misconduct was in relation to a study on a drug to treat a blood disorder in children that Koren and Olivieri had once collaborated on. Olivieri identified risks that the drug was ineffective and caused liver damage, and voiced her concerns despite legal warnings from its maker, Apotex. Koren differed and, contrary to accepted norms, published an article on the drug using data from other researchers, including Olivieri, without their knowledge or consent.”

“Koren had received hundreds of thousands of dollars in funding from Apotex after the company had terminated the drug trials in its efforts to prevent Olivieri from disclosing risks to patients, as well as the hundreds of thousands of dollars in funding he had received during the trials,” the newsletter reported, citing an journal article by the authors of “The Olivieri Report.”

Apotex marketed a generic version of Paxil, or paroxetine.

The penalty had been jointly proposed to the discipline committee through prior agreement between Koren’s attorney and counsel for the college, the Bulletin noted. In its decision, the committee said it was “deeply troubled by this case” and “seriously considered administering a more severe penalty” than that proposed, as it wished “to express unequivocally its condemnation of Dr. Koren’s misconduct.”

Glaxo Money Still Flowing

In a December 14, 2009 report on Pharmalot, Ed Silverman noted that Glaxo had published a list of fees paid out to US healthcare professionals for speaking and consulting services for the three month period of April 1, 2009 to June 30, 2009. “By its own tally, Glaxo paid $14.6 million to approximately 3,700 US docs and other healthcare professionals,” he reported.

Although Glaxo paid out millions of dollars over the years to the doctors discussed in this article, not one of them was called to testify as an expert in the first birth defect trial.

(The Paxil Birth Defect Litigation Update Series is sponsored by the Houston law firm of Vickery, Waldner and Mallia at http://www.justiceseekers.com)

Filed under: 2010, Birth Defects, CASPPER, front groups, ghostwritten, Glaxo, Kilker, KOL, Paxil, Paxil birth defect litigation, pregnant, SSRIs, Study 329, Vickery

Cold Case Files – Paxil Birth Defects Litigation

Evelyn Pringle March 2, 2010

Almost like an episode of the TV show, Cold Case Files, the first Paxil birth defect trial was dominated by a story about what happened to the rat pups that died around 1979 and1980, involved in a study in which Paxil was being tested on pregnant female rats.

The animal studies giving Paxil to rats and rabbits were conducted by a Danish company called Ferrosan before the drug maker, that later became part of GlaxoSmithKline, purchased the drug.

The family’s lead attorney in the case of Kilker v Glaxo, Sean Tracey from Houston, brought in the world-famous neuropsychopharmocology expert from Wales, Dr David Healy, to testify extensively about rat pup study 295.

In summary, Healy told the jury that all the rat pups born to mothers who received Paxil were dead four days after they were born, while eighty-eight percent of the pups not exposed to Paxil were still alive on day four.

In fact, of the 415 rat pups born to mothers who received Paxil, Healy testified that, “One in every ten or actually maybe more like possibly one in every eight or so were born dead.”

As far as he could make make out, all the rats were not autopsied, Healy said, so the question was why the pups died.

“It’s clearly the drug that has caused the death,” he told the jury.

“One of the possible reasons for their death is they’re born with birth defects that lead to them actually dying early in infant life,” he testified. “A responsible approach to data like this is to investigate it further and find out just what the cause is.”

Doctor Suzanne Parisian, a former FDA scientist, also served as an expert for the plaintiffs. She testified that the first safety signals that indicated Paxil could cause birth defects were seen in the animal studies conducted in 1979-1981 period, as well.

Parisian said the studies showed birth defects, embryos that died, and rat pups that did not survive.

Adam Peavy, of the Houston firm of Bailey, Perrin and Bailey, handled her testimony. While testifying, Peavy had Parisian review comments in a memo by a Doctor John Baldwin to Glaxo in 1980, discussing the Ferrosan studies, which stated: “There remains the possibility that this compound could be teratogenic at high-dose levels.”

“We need to ascertain whether Ferrosan have conducted or are conducting or intend to conduct a peri- and postnatal study and a neonatal acute toxicity study,” Baldwin wrote.

Based on her review the documents, Parisian told the jury, Glaxo never ascertained whether Ferrosan did the studies and Glaxo never conducted the studies.

As far as she knew, the company never told the FDA about Baldwin’s statements either, she said, but “they should have.”

On October 13, 2009, the jury in Philadelphia rendered a verdict against Glaxo and awarded the family $2.5 million. More than 600 Paxil birth defect cases are pending in the multi-litigation in Pennsylvania.

Paxil Worse Than Cocaine

In May 2009, a paper was published by a Doctor Sloot and the complete version of the study came out in September 2009. During closing arguments, Tracey told the jury, the “Sloot study is probably the single most problematic document in this case for them because it could have easily been done.”

“They would have known that the drug was a clear teratogen. It was more powerful than cocaine,” he said. “And it was more powerful a teratogen than even the control or as powerful as the control retinol that everybody in this courtroom, everybody that has testified, has said that drug is a teratogen.”

“And had GSK done the studies that Baldwin told them they should do, or a study like Sloot, any time before they started marketing,” he told the jury, “we wouldn’t be here.”

Retinol is an active ingredient in Accutane, a pregnancy Category X drug, meaning it is known to cause birth defects and is not to be used by pregnant women.

During his testimony, Healy was asked to tell the jury what the Sloot study was seeking to do.

“Schering-Plough had acquired a different European company called Organon who had a number of drugs which were serotonin reuptake inhibiting drugs,” he explained.

“One of the things that Schering-Plough wished to find out was could they bring any of these drugs to the market,” he said.

“What they then did was to do reproductive toxicology studies on these drugs that were new to them, plus on, I believe, all of the SSRI drugs that were on the market, plus a number of drugs which also inhibit serotonin reuptake, like cocaine, and they threw into the mix one or two more drugs, one that was known not to cause birth defects and one that was known to cause birth defects closely related to Accutane,” he told the jury.

They had a “particular system to look at the impact of all these drugs on the developing fetus to see were there any indicators of risk,” he said, using rat fetuses.

The study “found that Paxil, of all the SSRIs on the market now, was the most likely to cause birth defects and caused birth defects at the same rate as Accutane did,” Healy said.

He was asked how Paxil did in the study compared to cocaine in terms of potency.

“It was much more likely to cause birth defects than cocaine,” he said. “Cocaine in this particular system was much safer than Paxil.”

On September 21, 2009, the jury also heard testimony on the Sloot study from Doctor Shira Kramer, an epidemiologist. “Doctor Sloot’s paper demonstrated that Paxil was a clear teratogen,” she said, “that it was not just an effect of developmental or birth-weight related effect, that it was a direct teratogen, and that there was a spectrum of defects observed in rat embryos at low doses, establishing that it was a very potent teratogen, more teratogenic than cocaine and retinol, clear teratogens in their own right.”

Parisian told the jury that the Sloot study, conducted in 2009, could have been conducted in 1981 and it would have answered the question that Dr Baldwin was asking about embryotoxicity in 1980.

“If you use that type of a study, it specifically addresses embryotoxicity,” she told the jury.

Paxil Journey to Japan

Although Paxil was not approved in Japan until 2000, a couple years after it was approved in the US in 1992, Glaxo began looking into marketing the drug in Japan and meeting the requirements for approval by the Minister of Health and Welfare (MHW), the Japanese equivalent to the FDA.

“And the Japanese, they suspected, were not going to accept their dead rat pup studies,” Tracey told the jury in his opening statement on September 15, 2009.

“And so GSK began discussions internally,” he said. “Internally among themselves they said: What are we … going to do if Japan makes us do the studies to find out why the rat pups died?”

While Healy was testifying, Tracey introduced a February 9, 1994 memo to Glaxo employee Charlie Fake, and copied to others, from Jenny Greenhorn titled, “Paroxetine Japanese reprotox requirements,” and asked Healy to explain the meaning of “reprotox.”

Any “agency in the world has a requirement from the pharmaceutical companies to look at the reproductive toxicities of a drug,” Healy said. “This includes the impact of the drug on fertility, as well as the potential for the drug to cause birth defects.”

The first sentence of the memo stated, “we have reviewed the three plans for meeting the Japanese reprotox requirements for their regulatory implications elsewhere, should a valid, significant positive i.e., adverse, result be obtained.”

The next two sentences in the memo stated: “The conclusions reached within regulatory are summarized below.”

“It should be noted that there is little or no regulatory information in this area, and we know of no precedents, neither have we consulted with experts outside of the company due to sensitivity of the issue,” they wrote.

“These are, therefore, only our opinions of the likely consequences of positive findings in such studies,” they pointed out.

“What you want from this kind of study is that there is no harm to the fetus,” Healy explained to the jury.

“A positive outcome means there has been a harm,” he said. “So they’re here trying to plan if things go wrong, how do we handle it.”

Healy testified that, “regulatory implications elsewhere,” refers to the fact that the market in Japan is extremely small and the market in the US is huge. “They really have to work out if it is a worthwhile risk being asked to do particular studies which might cause a problem which we would then have to report back to the FDA,” he said.

“And the implications for the market here in the U.S. may mean that it’s just not worth our while trying to go to Japan at all,” Healy testified.

Indeed, throughout page one they discussed the “consequences” of positive findings in the plans for “such studies” if done for Japan. For instance, they stated at one point: “A change in the pregnancy category from B to C is a possibility.”

“This may have commercial implications as the other SSRIs have a B categorization,” they pointed out.

After reviewing the first page and explaining several statements to the jury, Healy was asked whether it appeared that anybody had considered the safety of Paxil. “It appears to me actually as a scientist that this is the opposite to what one would do,” he said, “if the point of view from the scientific end of things is we want to find out what happens.”

What “seems to be happening here is there is a much more business approach which is, well, we don’t really want to know what happens,” he said. “Because if we know, then there are commercial implications.”

For Plan II, they also discussed the “problem” and stated: “A positive finding in the Japanese style Segment II study would be more of a problem since in this case it is undoubtedly exposure during early pregnancy that is of concern for women.”

“A strengthening of the labeling might be likely, EG, women of childbearing potential should not take the drug unless they know they are not pregnant and are taking adequate contraceptive precautions,” they warned. “Worst case, but just possible, contraindication of women of childbearing potential.”

“What they’re saying here is that an awful lot of women clearly don’t know they’re actually pregnant until a few weeks into the pregnancy,” Healy had explained earlier, regarding what was meant by “contraindication” for women in childbearing years.

“Those early few weeks are the period when the harms may happen,“ he said. “And in the case of a drug like this where … there may be a risk of being hooked to the drugs so you cannot get off it if you think you may have become pregnant, then clearly this all becomes extremely risky as it goes on.”

And in this paragraph, they reiterated: “Again, a change in U.S. Pregnancy category from B to C is likely.”

“A positive in the Japanese Segment III would be less of a problem,” they wrote, “since it defines the critical period as the third trimester which authorities would feel more comfortable with.”

“However,” they warned, “they may insist on animal findings being added to the labeling with additional comments and this is certainly the case with the United States, Canada and Australia who have extensive product information.”

In the last paragraph for Plan III, they stated: “This is the same as Plan I, but the lower doses make findings much less likely.”

Again, “this looks like risk management,” Healy told the jury.

“What seems to be happening here,” he said, “is an effort to design a particular kind of experiment that would look like we have been doing things but we’re trying to control the risks, things that could go wrong.”

“So that people will say, well, yes, they have done the experiments, but it didn’t show a particular problem,” he told the jury.

Later in the memo, they stated: “Obviously, conducting no more studies and arguing the case with the MHW would have no regulatory implications elsewhere unless our arguments fail and the MHW requests us to do the type of study we wish to avoid.”

And then it went on to warn: “If they do request a study, there’s a potential problem in that they may direct/insist on our performing a study to their preferred design.”

“At least we are now in the position of being able to do the study we chose and then defending it,” they wrote, with an exclamation point.

After having Healy discuss what was meant by comments throughout the memo, Tracey asked: “Is there anything in this entire document you see, Dr. Healy, that appears as if there is a study being designed by this company to find out the truth about their drug in pregnancy?”

“No, there isn’t,” Healy replied.

While Parisian was testifying, the jury was shown an email dated March 30, 1994, with a discussion about the Japanese government asking for specific information about behavioral changes in babies exposed to Paxil and the protocols for a study that was being designed to respond.

The last sentence read to the jury stated: “Gwyn Morgan will be responsible for the review and the analysis of the protocols to ensure that a likelihood of any potential negative outcome is minimized.”

The goal of pharmacovigilance is not to minimize risk, “particularly when the Japanese government is concerned about the risk,” Parisian told the jury.

The purpose of doing pharmacovigilance and safety surveillance, in terms of toxicology, she said, “is to identify risks so that it can be addressed.”

“And in terms of pharmacovigilance, animal study feeds into the information you have about outcomes of infants,” she told the jury.

In 1997, Glaxo teratologist, Patrick Wier, conducted the rat study, with Segment one comparable to women in the first trimester of pregnancy, and Segments Two and Three comparable to women in the second and third trimesters.

Each “type of study in a rat is trying to simulate what would occur in a woman at those different stages,” Parisian explained to the jury.

Rats are only pregnant for about 22 days, or 7 to 8 days per trimester, she said.

Wier’s study was not designed to find out whether Paxil was a teratogen. It was a behavioral study, “which the ultimate goal was to keep pups alive so that you could look at changes in their behavior,” she pointed out.

“They designed the study to fail,” Tracey told the jury in his opening statement.

A 1997 document stated the doses “have been adjusted accordingly and the risk is now considered as minimal and acceptable,” he said in closing arguments.

But the study did have rats that died with birth defects. Specifically, a ventricular septal defect (VSD), was found in an edematous (swollen) rat; one of the same defects that Lyam Kilker was born with.

The conclusions in the report did not disclose whether the rat with VSD was born to a mother exposed to Paxil. “It was in the text and it was also in appendix 9,” Parisian said.

She testified that the 1980 Ferrosan study also had two edematous rats but they were not autopsied. There is “no information as to why those two rats were edematous,” she stated, “but the company listed them as major malformations.”

“They also had malformations in their rabbit studies,” Parisian reported.

Testimony Debunked

In closing arguments, Tracey pointed out that Patrick Wier had testified that he knew why the rats died because he did a study in 1997.

“Let’s see whether or not that’s true,” he told the jury.

He then reread a memo, gone over during the trial, from July 10, 1998, a year after Wier did his study, which stated in reference to Wier: “Have you worked with Patrick on the concern about the REPROTOX work having been conducted in the seventies? If no, please initiate discussions and set up plans for the MHW discussion. If yes, I would like to know how we intend to justify the validity of these studies and the arguments for rebutting why we should not repeat them.”

“I don’t know how I can take that out of context,” Tracey told the jury.

“If they knew the reason,” he asked, “why do they need to defend or justify the validity of the studies?”

“Why do they have to have an argument for not repeating them if they are fine and … everybody knows why the rats died?,” he pointed out.

He noted that Wier’s memo said, “all we really need is a plausible explanation in case the regulators ask us why the rats died.”

One thing is undisputed in this case, Tracey said. “They never did the test at the higher level with the rabbit to figure out whether or not this drug was a teratogen.”

“If what a drug company really wants to know is whether or not their drug is dangerous, they test it. They don’t avoid tests,” he told the jury in closing arguments.

“Because the negative result will cost us money is not a defense to not finding out the truth about your drug,” he pointed out.

Secret Reports

During her testimony, Parisian explained that once a drug is approved it is the manufacturer’s job to do pharmacovigilance.

The clinical trials done to get a new drug approved typically do not have women that are pregnant, she testified. Once a drug is marketed, the company will start getting data about mothers who are pregnant and their babies and it’s “the duty of the manufacturer to monitor that,” she said.

In the case of Paxil, the trials excluded both women who were pregnant and women who could become pregnant because the animal date suggested that there was a risk, she noted, citing a 1984 FDA letter.

While testifying, Peavy had Parisian review a 1997 internal Glaxo document titled, “Paroxetine: Pregnancy with Abnormal Outcomes,” discussing the reporting of birth defects in Japan.

The document stated in part: “There have been 17 reports of congenital abnormality reports to the MHW.”

It also stated: “The company should consider it important that this many cases have appeared.”

The document contained a table with a list of adverse event reports collected on birth defects and birth outcomes, based on an internal review of information received about pregnancies, that showed 32 reports of abnormal outcomes with congenital anomalies.

The company had information on a total of 635 pregnancies in general but only knew the outcomes for 315 infants. “So about half they don’t know what happened,” Parisian explained.

You don’t “know what has happened to those babies at all,” she stated.

Parisian testified that Glaxo internally had reports that looked at all birth defects known to the company, which she had reviewed prior to the trial.

One of the reports was titled, “Paroxetine in Pregnancy,” on adverse events and pregnancy outcomes.

This analysis had a cutoff date of May 1996, and would include the knowledge of the company on pregnancies from the date Paxil was approved in 1992, through May of 1996, Parisian said. The table in this report showed 36 cases of abnormal or congenital outcomes.

This report was never submitted to the FDA according to the testimony of Glaxo employees, Parisian said, but it should have been because it “is safety information.”

In 1998, Glaxo prepared another internal report titled, “Paroxetine and Reports of Congential Abnormalities,” with a cutoff date of November 1997, that showed 42 cases of congenital anomalies.

Parisian said this analysis was also never submitted to the FDA, as far as she knew, but under the rules it should have been.

Peavy then had Parisian review the draft version of the report, showing the same cutoff date and 42 congenital anomalies. On page 5, it stated: “The incidence rate of congenital abnormalities as observed in the data reported in this document is 13.3 percent.”

But the draft version contained the following statements that did not appear in the final report: “A figure much higher than that reported by birth-defect monitoring bodies. Taken at face value, this represents an alarming finding.”

Under FDA rules, drug companies are required to report alarming findings to the FDA, Parisian said. “They are also required to report any kind of safety analysis that they have done internally like this to address an issue about safety.”

In fact, Peavy produced a 1984 letter to the company from the FDA, which specifically stated that the agency wanted to be informed about any “alarming findings” in either human or animal studies.

The 13.3 percent incident rate of congenital abnormalities was between six and seven times the 2.5 percent overall birth defect rate you would expect to see for births in the US, Parisian told the jury. The CDC uses a 2.5 percent background rate.

A 13.3 percent rate “would be a type of signal that a manufacturer should address,” she testified.

Another exhibit reviewed for the jury showed the Japanese had received 27 reports of congenital abnormalities since December 1998 and they were requesting more information about safety, and included emails written by Glaxo employees, Ann Bell and Narita San.

An email written by Narita San stated in part: “This is unexpected number of reports, because only 50 cases were reported in the previous position paper. I think we have to take this abrupt increase of reports into consideration to the reply.”

Parisian explained that “the Japanese are saying that they have received 27 reports of congenital anomalies and they want an update on the prior information.”

In 2000, another internal report of the adverse events for pregnancy outcomes was completed by Doctor Stephen Hughes, Ms Easterbrook and Ms Caley, the worldwide clinical safety group, updating the report made in 1998, Parisian said.

The analysis, with a cutoff date of March 2000, showed Glaxo knew the outcome of 656 pregnancies, out of a total of 1,189 known Paxil pregnancy exposures. By then, there were 79 reports of congenital abnormalities, meaning 12 percent of pregnancies with known outcomes resulted in birth defects.

It was possible that some of the babies in the pregnancies with unknown outcomes also had birth defects, Parisian said. “They are unknown what they had.”

While testifying, Parisian was asked to explain the general rule of “underreporting.”

It is general “knowledge that adverse events that the FDA receives are underreported,” she said. “The FDA’s numbers range from 1 to 10 percent.”

So the FDA looks at the adverse event reports they receive as the tip of the iceberg, “maybe 10% of the reports that are actually out there,” she pointed out.

If talking about underreporting figures for 79 cases of congenital defects, she said, “that would be 1 percent maybe to 10 percent, which would be 7,900.”

“That would be babies that actually lived to getting born,” she told the jury. “That’s nothing to do with the miscarriages and what is not known.”

The reports discussed during her testimony, “were not your classic safety analysis,” Parisian explained. They were a “reporting or a tabulation of what information the company had.”

They were being prepared for the Japanese because the Japanese government wanted safety information on pregnancy outcomes and they were also concerned about “late pregnancy, what the behavior would be of the baby when the baby was born if the mother was taking Paxil,” she told the jury.

But under the rules, Glaxo was required to turn over any internal safety reviews, reports, and analysis to the FDA, Parisian told the jury, “particularly with pregnancy, which the FDA has been asking for information since the product was approved.”

None of the analyses were turned over to the FDA, according to the testimony of Glaxo employees, Parisian said.

Under cross-examination, Glaxo attorney, Joe O’Neil, asked Parisian to identify the FDA regulation she was referring to in stating the reports should have been submitted to the FDA. “I would specifically use (21 CFR) 314.81,” she said, “FDA talks about issues with children, information about children that they are to receive that information.”

“Also, as a postmarket study asked (for) by the Japanese which is the 2000 report,” she stated. “That would be under (21 CFR) 314.80.”

While cross-examining Parisian, O’Neil put up a power point slide listing the FDA approvals of Paxil and Paxil CR, the controlled release version, for additional indications between the initial approval for major depression disorder in 1992 through 2004, including panic disorder, obsessive compulsive disorder, general anxiety disorder, and PSTD.

Several times, Parisian noted that Paxil was not approved for use by pregnant women. O’Neil pointed out that for each new indication, FDA approved the label and Paxil was never contraindicated for use by pregnant women on the label.

Under redirect examination, Parisian testified that when Glaxo applied for approval of the new indications, the FDA was not given the internal analysis of birth defects available at the time or told about Dr Baldwin’s comments on the early animal studies.

Although the 2000 report with 79 cases of birth defects was supposedly done for the Japanese government, it was never given to the Japanese, Tracey told the jury in closing arguments. “It wasn’t given to the people it was prepared for,” he said.

And after the report in 2000, Glaxo stopped doing the pregnancy analysis, he said. “For the next five years we have nothing,” he told the jury. “We don’t have any reports. We don’t know how many birth defects are reported to them.”

FDA Stamped Paxil Label

Glaxo’s lead attorney in the Kilker trial was King & Spalding partner, Chilton Varner.

In her closing argument, Varner stated: “FDA repeatedly reviewed and approved the safety of Paxil, including the scientific data and the animal tests, 13 different times between 1992 and 2004.”

In his final summation, Tracy told the jury: “Ms. Varner has said time and time and time again the FDA rubber-stamped” the label.

“What we know is the FDA didn’t have all their information,” he said.

“The FDA didn’t know what they thought about the animal studies,” he stated. “The FDA didn’t know the analysis they had done.”

“And one thing you need to understand is to this day, the FDA still hasn’t seen these documents,” Tracey told the jury.

“To this day, only my experts have seen the internal GSK documents,” he said. “To this day, you are the only people outside of this courthouse that have laid eyes on these documents.”

“These documents were under seal until this trial began,” he pointed out.

(The Paxil Birth Defect Litigation Update Series is sponsored by the Houston law firm of Vickery, Waldner and Mallia at http://www.justiceseekers.com)

Filed under: 2010, Birth Defects, ghostwritten, Glaxo, Kilker, KOL, Paxil, Paxil birth defect litigation, SSRIs, Vickery

Over Six Hundred and Counting – Paxil Birth Defect Cases

Evelyn Pringle March 8, 2010

Since Paxil came on the market in 1992, there have been three separate types of failure to warn lawsuits filed against GlaxoSmithKline over Paxil; birth defects, suicide, and addiction.

Roughly 150 suicide cases were settled for an average of about $2 million, and about 300 cases involving suicide attempts were settled for an average of $300,000, according to a December 14, 2009 report by Bloomberg News. Glaxo paid an average of about $50,000 each to resolve about 3,200 cases linking Paxil to addiction problems. The drug giant has also paid about $400 million to end antitrust, fraud and design claims, Bloomberg reports.

All total, Glaxo has paid out close to $1 billion to resolve Paxil lawsuits since the drug came on the market in1992. The company’s provision for all legal matters and other non-tax disputes as of the end of 2008 was listed as $3.09 billion in its annual report.

The first birth defect trial, in over 600 cases filed, resulted in a verdict for the plaintiffs on October 13, 2009, and an award of of $2.5 million in compensatory damages for the the family of Lyam Kilker, who was born with three cardiac birth defects after his mother took Paxil while pregnant.

In the Kilker trial, Glaxo’s lead attorney was King & Spalding partner, Chilton Varner, and Sean Tracey, from Houston, led the family’s legal team.

Andy Vickery, of the Houston firm of Vickery, Waldner and Mallia, is the lead attorney in several Paxil birth defect cases. The first case set for trial is unique in that it involves, Delaney Novak, an infant born with heart defects on April 4, 2002, to Laura and Derek Novak, after Laura was prescribed Paxil off label for migraine headaches.

The Novak case is also unique among the Paxil birth defect cases because Delaney’s parents had their insurance with United Healthcare, and Laura was part of the study that Glaxo contracted for, which resulted in the initial warning letter about birth defects in September 2005.

According to Vickery, Glaxo conducted a study on Wellbutrin (bupropion), another antidepressant, after discovering a possible link to birth defects. “The review found no problems with Wellbutrin, but discovered that a significant number of mothers who had been prescribed Paxil (nearly twice as many as those who had not taken the drug) had children born with heart defects,” he says.

Doctors Ra-id Abdulla, David Healy, Shira Kramer and Suzanne Parisian testified as the experts for the plaintiffs in the first trial. All told the jury they believed Paxil caused Lyam’s heart defects. Doctors Abdulla, Healy and Kramer are also expert witnesses in the Novak case.

Ingenix Study in First Trial

The Ingenix study, with lead researcher, J Alexander Cole, was conducted using data from the Ingenix Research Data Mart, containing insurance information from UnitedHealthcare. The study was not supposed to look at Paxil.

During the testimony of several witnesses in the first trial, the jury was shown a February 7, 2003 email in which Glaxo employee, Graham Cottam, stated that he had informed Anne Bell, the project leader for Paxil, about plans to do the Ingenix pregnancy study on Wellbutrin, and “Anne wanted to be sure that we will not be looking specifically SSRIs or Paxil.”

Doctor Suzanne Parisian, a former FDA scientist, testified that the initial 2002 proposal was “to do a large database study for Bupropion in pregnancy.”

There was “nothing that addresses Paxil,” she told the jury. The “procedure had never been designed to specifically look at Paxil.”

But when the data was broken out for Paxil in the original study, it “showed the increased risk and the pregnancy was changed to Category D,” she explained.

The FDA later requested that Paxil be studied, according to the testimony of Glaxo employees and documentation, she said.

The famous neuropyschopharmacologist and professor of psychiatry from Cardiff University in Wales, Dr David Healy, explained that Glaxo had hopes that the study would show Wellbutrin as an antidepressant that did not cause birth defects and the company could apply to the FDA to have it classified as a pregnancy category B drug instead of a C.

“It would give the message,” he said, “that this of the drugs we have available to use for women of childbearing years, this would be one of the safer ones.”

Healy told the jury that there was “no reason from the scientific point of view why they would not want to also look at Paxil.”

“And this appeared to be the FDA’s view,” he said, “because FDA said, well, you looked at Bupropion, why don’t you look at Paxil, also,” a couple years later.

When asked whether by the year 2003, he could think of any scientific reason not to do a pregnancy study with Paxil, Healy replied, “No, I can’t.”

In fact, Tracey showed the jury an internal company email written by a Glaxo employee two years later in August 2005, around the time that the results on Paxil from the Ingenix study came out, who asked the question: “Why hasn’t the company gathered data on this until now, 13, I think, years after the product was approved?”

In the case of the study on Wellbutrin, there were only 16 reports of birth defects that indicated there was a signal to do the study, Parisian told the jury. While an internal analysis conducted by Glaxo on Paxil in 2000, showed 79 cases of birth defects.

In September 2005, the conclusions of the Ingenix study were: “The use of paroxetine in the first trimester of pregnancy was associated with an increased risk of congenital malformations compared with other drugs.”

“To your knowledge, prior to 2005 did GSK ever do a single epidemiological study to determine whether or not Paxil caused birth defects?” attorney, Adam Peavey, asked Parisian.

“Not that I have seen,” she said.

Ingenix Downside

During the testimony of Dr Shira Kramer, an epidemiologist, Tracey put up a slide on the Cole paper that was published in 2007.

The paper was on a study conducted by epidemiologists who were employed by Glaxo to do the research, Kramer explained. It was a continuation of the Ingenix study that looked at Wellbutrin and then Paxil. One of the co-authors was Sara Ephross, an employee of Glaxo.

Kramer was asked to explain the importance of the Cole study. “First of all,” she said, “it was a cohort study comparing … people exposed to Paxil … to people who were exposed to other SSRIs.”

“So one very key thing for you to remember is that here the … unexposed group is not people who were not exposed to SSRIs, they were exposed to SSRIs,” she told the jury.

“That’s a very important point,” she said, “because if SSRIs are a risk factor for cardiac defects, birth defects, then the relative risk that will be generated in this study is going to be lower than it normally would if truly people were unexposed to SSRIs.”

“The other thing that is important to keep in mind,” she told the jury, “is that the information was obtained from an administrative claims database called the Ingenix Research Data Mart. “

“There was no individual, either examination or interviewing of anyone,” she explained. “The information was extracted from administrative claims data that was available.“

“The other thing that’s important,” she said, “is that initially the population that was studied covered the years 1995 to 2002, and then after the fact an additional two years were added to the study.”

“The published results, based on all of the years that were eventually included in this study, were an odds ratio for all cardiovascular malformations related to Paxil exposure of 1.46, which means that individuals who took Paxil were at 46 percent increased risk of their child having a cardiovascular malformation diagnosed at birth compared to individuals who took other, other SSRIs,” Kramer explained.

“In the second odds ratio of 1.68,” she said, “showing a 68 percent increased risk, now we are comparing women who took Paxil either alone or in combination with another SSRI, compared to the other SSRI group, either alone or in combination with other SSRIs, mono- or polytherapy.”

The published study contained an asterisk that said: “An interim analysis performed by Cole, et al, using births occurring between ’95 and 2002 found an odds ratio of 2.0 for the association between first trimester Paxil use and cardiac birth defects.”

Kramer was asked to explain what that statement was referring to. “Initially, the study was designed to include the years 1995 through 2002 with a sampling ratio of controls to cases of 7 to 1,” she said. “That was the protocol.”

“And when that analysis was done, the odds ratio, instead of being 1.46, which ultimately is what was published, was actually higher, it was 2,” she told the jury.

“That means that the exposed group had a risk of a child with a cardiac malformation two times that of the group not exposed to Paxil,” she added.

The odds ration got smaller when the Glaxo researchers, the authors of the study, “added in two additional years of data with a different sampling ratio,” Kramer explained.

It is not appropriate for an epidemiologist to do that, she said, because “you are changing the rules after you look at the data.”

It “really raises the questions as to, are you trying to influence the data,” she noted.

“I can say very clearly,” she told the jury, “that that is not considered to be appropriate conduct, scientific conduct. “

“What you are supposed to do is set up a study protocol in advance and follow it, and not change it after you have looked at the results,” Kramer explained.

It is not appropriate to find out the results and change it in the middle, she said, “for obvious reasons, it looks like you are manipulating the data to make it come out looking a certain way.”

“And if you want to do an unbiased, fair study,” she told the jury, “the only appropriate plan of action is to develop a study protocol ahead of time, to follow it, and to analyze the results and not to fool with it, not to fiddle with it and not to change it.”

While testifying, Kramer explained the meaning of “underpowering” a study. You need to have “a sufficient number of people in a study in order to test a certain research question,” she said.

“And if you are going to apply statistical tests to the data that you generate,” she told the jury, “you need to have enough people in that study to have generated enough cases of the outcome and you need to have enough people who are exposed.”

“Now, this case,” she said, “we have got a relatively rare exposure to Paxil, we have a relatively rare outcome, which is congenital cardiac birth defects, so you need to study very, very large populations in order to achieve statistical significance at these levels that we have been discussing.”

She said the “investigators, the research team,” dictates the size of the study.

Kramer went over the reasons why the odds ratio in the Cole study might be attenuated, or lower. It’s “very clear that there are certain characteristics of this study that are making this odds ratio probably lower than it really would be given certain characteristics of the study design,” she told the jury.

“One of the them is that the controls are really not unexposed to the SSRIs,” she said. “They are exposed to drugs in the same class.”

We have “observed in epidemiological literature that other SSRIs are associated with an increased risk of cardiac malformations,” she told the jury. “Therefore, it is likely that since that’s the comparison group, we have got an odds ratio in this study that’s lower than it probably would be.”

The second reason was that the analysis only included live births. “So you are missing fetuses who were miscarried,” she said. “And then there are many miscarriages that are due to birth defects.”

“You are missing fetuses that are aborted, electively aborted, because of known cardiac or other congenital malformations,” she told the jury. “You are missing stillbirths.”

And with a follow up for only nine months, she said, “you are missing congenital cardiac defects that aren’t detected until later.”

“So you have got a fairly substantial population that is not really being captured in this study of exposed fetuses,” she pointed out.

Closing Recap

During closing arguments, Tracey reminded the jury about the email with Anne Bell’s statement to make sure Paxil was not included in the Ingenix study, and said: “This document … two years before this child is born, they are affirmatively saying: We do not want to look at Paxil in pregnancy.”

In her closing argument, Varner told the jury: “Now, Mr. Tracey has talked to you about Anne Bell this morning.”

“He has said that GSK would have done anything to avoid looking at the risk for Paxil,” she pointed out.

“Well, ladies and gentlemen,” Varner said, “GSK funded the study that did look at Paxil for the risk and published preliminary findings in August of 2005.”

As soon “as even a possible link emerged in all of 2005, GSK reacted promptly and proactively to notify both FDA and doctors,” she told the jury.

“It went immediately to FDA. It immediately changed its label,” she said. “And it immediately sent out letters to doctors telling them about the changes.”

In his final summation, Tracey told the jury, “I want to talk to you about the Ingenix study because Ms. Varner said something that is very, very important.“

“She said when they found out what she says is August of 2005, within 21 days, they changed the label. Within 21 days, the doctors got the news,” he recounted.

What “she forgets to tell you is that two years prior to this, Anne Bell said, Don’t study the drug,” Tracey told the jury.

“Had they not listened to Anne Bell,” he said, “had they studied the drug in 2003, Michelle David wouldn’t be sitting here because the warning would have gone out like that.“

“We would have been two years ahead of the game,” he pointed out.

“GlaxoSmithKline did not want to study the drug,” Tracey told the jury. “The FDA made them study Paxil.”

“It was not some sort of voluntary we’re just a good drug company trying to get along,” he said. “It was we don’t want to study it and they’re forcing us to study it.”

Paxil Off-Label Promotion

Paxil is not FDA approved for use by pregnant women, so all mothers who gave birth to infants with heart defects received the drug off label. In Andy Vickery’s first case set for trial, Delaney Novak was born with heart defects after his mother, Laura, was prescribed Paxil for migraine headaches, another unapproved use.

Dr Dee Mangin is an expert witness in the Novak case. Her research and published work has focused on rational prescribing, and the influence of drug company promotion both to physicians and direct to consumers. She submitted a report on October 13, 2009, which outlines Glaxo’s off label promotion of Paxil around the time of Laura’s pregnancy.

In her report, Mangin defines off-label use as the “practice of prescribing drugs for a purpose outside the scope of a drug’s approved label – often an unproven use or one that has not been widely tested.”

“While it is legal to prescribe off label in the United States, it is illegal for companies to promote off label use,” she notes.

“The risks of off label promotion,” she says, “are that it could lead to exposure of patients to the risks of a medicine for no benefit, and furthermore they maybe denied other more effective treatment.”

“GlaxoSmithKline from 2000,” Mangin says, “mounted a multifaceted and targeted national promotional campaign that employed explicit strategies designed to promote sales of Paxil in pregnant women and women of reproductive age.”

An exhibit cited in the report from a “Paxil Tactical Marketing Plan in 2000,” states: “New Paxil data with high media interest, hot flash, postpartum, depression, pregnancy, and lactation will position Paxil as the drug of choice for women.”

“One of the known reasons that physicians change their prescribing behavior is as a response to the volume of evidence containing the same message that the physician is exposed to,” she wrote. “The so-called “Carpet Bombing” technique used in the Paxil campaign feeds directly into this.”

“There are a number of strategies companies can use to highlight use for off label conditions including distribution of individual scientific articles discussing the off label indication and use of the drug as well as mentions of off label use by key opinion leaders in continuing medical education,” the report explains.

“In relation to the off label prescribing for migraine,” Mangin says, “there is no evidence of any effectiveness over placebo for SSRIs in migraine prevention.”

Yet a paper titled, “Paroxetine in the Treatment of Chronic Daily Headache,” by Carol Foster, MD, and Jacklyn Bafaloukos, RN, that was distributed to doctors, specifically states: “The dramatic improvement in the patients in our study suggests that paroxetine appears to be a safe and effective drug for the treatment of chronic daily headache.”

“The strategies outlined where reprints about treatment of migraine with paroxetine, large numbers of form letters containing summaries of studies of use in headache were sent to physicians and detailing and providing free samples to physicians likely to treat women with migraine were therefore encouraging use of Paxil and exposure to its risks when in reality it is no more effective in this situation than a sugar pill,” Mangin reports.

Encouragement “of unapproved use for migraine further attempted to expand the market beyond that which was medically justified and likely to lead to unnecessary exposure to the risks of Paxil,” she advises.

In an August 11, 2009 deposition, Laura’s doctor testified that Glaxo sales representatives would commonly leave reprints of articles on off label uses and salespeople did discuss the literature on the off label use of Paxil for migraines with him. One of the sales representatives visiting the doctor at the time stated in a deposition that it was his habit to distribute all such articles.

But most importantly, the doctor said he would not have prescribed Paxil to Laura had Glaxo told him back in 2000, or early 2001, that there was an association between Paxil and birth defects. He further noted that there was no benefit from Paxil that would outweigh the risks of birth defects and that he had not used Paxil in his practice since the Dear Doctor letter warned about birth defects.

Delaney suffers from a septal heart defect. “None of the information from the medical records of the family or their statements on potential genetic, environmental and pharmaceutical causes of heart defects indicates any other factor more likely to have caused her condition than the Paxil exposure,” Mangin points out.

“It is clear that if the prescribing doctor had been informed of the risk of heart defects, Laura Novak would not have been exposed to Paxil,” she notes.

In the report’s conclusion, Mangin states: “It is my opinion that this promotional campaign for Paxil was inappropriate given the scientific knowledge and what was known by the company at the time.”

“The degree of comfort with the use of this medication in the reproductive years and pregnancy is likely to be influenced by GSK’s misleading promotional campaign where concerns were minimized, efficacy was overstated, the idea of off label prescribing was seeded for migraine, and lastly the marketing specifically targeted a group at higher risk in terms of safety concerns – pregnant women and women in the reproductive age group,” she reports.

“This Paxil promotional campaign was irresponsible, and potentially disastrous from a public health perspective as it was likely to expose a much greater proportion of the population to these potential harms,” she concludes.

Glaxo’s Phone Book

During closing arguments on October 8, 2009, Tracey told the jury regarding Glaxo: “They have a telephone book full of doctors.”

Referring to an exhibit introduced during the trial, he said: “This is all the doctors that they pay to give speeches on their behalf to push their drug, to sell it, to convince other doctors to prescribe their drug.“

While Healy was testifying, Tracey had him go over some of names of doctors in the book that included Lori Altshuler, Vivian Burt, Lee Cohen, Charles Nemeroff, Jeffrey Newport, Zachary Stowe, Katherine Wisner and Kimberly Yonkers. None of these doctors appeared to testify on Glaxo’s behalf in the trial.

What “they did was aggressively market this drug to women,” Tracey told the jury.

All “these names of people that they ghost-wrote articles for to get the doctors … to sell the drug,” he noted.

Doctor Healy told you that “they altered the prescribing practices in this country,” he recounted. “What they set out to do, they succeeded in doing. They got doctors to prescribe the drug to women.”

“And they did it,” Tracey said, “by having seminars where they would put these doctors, experts in the field, on their payroll, that the doctors would go and listen to, unwittingly knowing what they are really hearing is a marketing campaign.”

In reference to another exhibit viewed during the trial, Tracy said: “This document describes that it worked. When the doctors came out, these are the comments they made after attending these seminars: Will prescribe Paxil to pregnant women. My comfort in treating depression in pregnancy has increased. Treating pregnant patients with confidence. Will feel more comfortable giving Paxil to pregnant women.”

In citing $765 million in the US alone, between 1997 and 2005, Tracey told the jury: “This is the number for over a nine-year period this company spent to convince doctors to sell their drug, to prescribe their drug to women of childbearing years.”

“And they got a heck of a return on it,” he said. “Net. After expenses. Almost 14 billion dollars for a nine-year period.”

“Out of the 700 million dollars they spent trying to sell this drug to people,” Tracey stated, “there is not one shred of evidence in the record about how much money they spent to try to figure out whether it was going to induce birth defects.”

“And as far as I can tell in the record,” he said, “after they bought it, they did one animal study and they didn’t spend another penny.”

(The Paxil Birth Defect Litigation Update Series is sponsored by the Houston law firm of Vickery, Waldner and Mallia at http://www.justiceseekers.com)

Filed under: 2010, Birth Defects, Glaxo, Kilker, KOL, Paxil, Paxil birth defect litigation, SSRIs, Vickery

Glaxo Birth Defect Litigation Reveals Paxil Promoters on Speed Dial

Evelyn Pringle February 23, 2010

In the first Paxil birth defect trial against GlaxoSmithKline, much of evidence focused on the doctors on Glaxo’s payroll involved in the corruption of the medical literature and seminars given to promote the off label use of Paxil with pregnant and nursing mothers.

On October 13, 2009, the trial of Kilker v Glaxo ended with a Philadelphia jury awarding $2.5 million in compensatory damages to the family of Lyam Kilker, after finding that Glaxo “negligently failed to warn” the doctor treating Lyam’s mother about the risks of Paxil and the drug was a “factual cause” of the child’s heart defects.

Glaxo’s lead attorney at trial was King & Spalding partner Chilton Varner, and the family’s lead attorney was Sean Tracey from Houston.

During his opening statement on September 15, 2009, Tracey told the jury that Doctor David Healy is “one of the most, if not the (most) world-recognized expert on pharmaceutical industry influence and the medicine, he is up there in the top five.”

Healy “is going to explain to you how GSK corrupted the medical literature,” he said, “how they used their money and influence to have doctors that they paid put out literature into the world so doctors … could read literature that looked like literature, looked like science, smelled like science, appeared to be science, from very important people, people that were on boards, people that were professors, people that published hundreds of articles.”

Healy is going to explain to you that what they didn’t tell people … “is, we are paying these doctors to do all these things,” Tracey told the jury.

“There is a book, it looks like a telephone book,” he said, “of names of doctors, influential doctors, on their payroll, the names of these doctors you will see on this literature that looks and smells like science.”

“And just coincidentally, this science that they are going to parade before you, all seemed to help them,” he told the jury. “Some of this happened in the last couple weeks before this trial started.”

Advisory Panels and KOLs

While testifying, Tracey had Healy explain the concept of key opinion leaders (KOLs) and drug company advisory boards.

“When a pharmaceutical company is bringing a drug to market,” Healy said, “a few years before they bring the drug to the market they look at the academic physicians in the field and work out who will be the key people who will be the advocates for the drug.”

“They recruit advisory panels for the drug, which will be senior figures within the field who they believe they will be able to depend on to persuade the rest of their colleagues to think seriously about using this drug,” he noted.

In explaining a “national” advisory board, Healy said, when “a drug comes to market, they will have a range of senior people in the field, it could be 10 or 12 different people from different parts of the country whom they think are going to be the most influential in helping to get their drug moving within the market here in the U.S. or the U.K.”

“Then there is a further group of people down below,” Healy said, “who are called the key opinion leaders or KOL for short.”

“These, again, are fairly senior doctors,” he told the jury. “These are the people whom it is thought will go out and give lectures on the drug to the doctors who are actually doing most of the prescribing of the drug.”

In the early 1990s, Healy was on a Paxil advisory board around the time the drug was launched in the UK. People who did not think Paxil was a great product would usually be dropped from the advisory panel, he told the jury.

In fact, Tracey produced a Glaxo memo that stated: “if after this meeting anyone on the advisory board who doesn’t passionately believe Paxil’s uniqueness for anxiety should quietly be replaced.”

Naming Names

During the trial, Tracey wanted Healy to specifically testify about Doctors, Charles Nemeroff and Zachery Stowe, and apparently Glaxo did not want the jury to hear the sordid tale because their attorneys strongly objected.

On September 16, Tracy argued his case to the judge in chambers outside the hearing of the jury. “Doctor Nemeroff is generally considered, or was before his fall from grace, the most powerful man in psychiatry in the United States,” Tracey told the judge.

“Doctor Healy is uniquely qualified to talk about Doctor Nemeroff’s role in the corruption of medical literature related specifically to Paxil as orchestrated by GSK and Doctor Nemeroff,” he argued.

“Same with Doctor Stowe,” Tracey said. “Doctor Stowe specifically carried out a campaign to market through GSK or GSK through Doctor Stowe to pregnant women and women of childbearing age.”

“I need to show the jury that an enormous amount of money changed hands between Stowe and Nemeroff and others,” he said, “and that all of these doctors were on GSK’s Paxil advisory board.”

“It goes to the credibility of these doctors,” Tracey pointed out.

“These are the doctors that are writing the literature that is out there in the peer-reviewed literature that doctors are relying on,” he told the judge.

These doctors were required ethically “by their universities to disclose to the Federal Government how much money GSK was paying them,” Tracey said. “They did not do that.”

He also wanted the jury to know that “Emory University has actually stripped Doctor Nemeroff of his chair over this very issue of failing to disclose payments from GSK,” he told the judge.

Tracey wanted to prove these allegations with testimony from Healy about Senator Charles Grassley’s investigation of Nemeroff and Stowe and the results that were made public. In the end, the judge refused to allow Healy to testify about the amounts Nemeroff and Stowe were paid by Glaxo, why Nemeroff lost the chairmanship, or the disciplining of Stowe.

“Whether or not Emory had a battle with them about disclosure is not relevant in my mind,”the judge told Tracey. “What is relevant is that they were prominent individuals who wrote in favor of this drug, that they were on the advisory board, that they received honorariums of money, and that he believes in his opinion that these articles are wrong that they wrote.”

“He can offer his opinion that they were wrong and why they were wrong,” he said. “I am going to keep out the argument about the doctors being sanctioned for failing to disclose.”

Nemeroff’s “credibility from Emory would involve a mini trial of the issue with Emory and him,” the judge said.

The Emory investigation, in fact, found Nemeroff was paid more than $960,000 by Glaxo, from 2000 through 2006, but listed less than $35,000 on his disclosure forms. All totaled, he had earnings of $2.8 million from speaking and consulting arrangements with drug companies between 2000 and 2007, but failed to disclose at least $1.2 million, according to Senate Finance Committee reports.

In 2008, Stowe was the primary investigator for a National Institutes of Health grant where the stated purpose was “to stimulate vigorous debate with the emphasis on the reproductive safety of antidepressant medications,” according to a June 2, 2009 letter to the president of Emory from Grassley.

Glaxo paid Stowe $154,400 for fifty-seven promotional talks in 2007. He also received $99,300 from Glaxo in the first ten months of 2008 for thirty-eight talks for antidepressants, according to Grassley.

During a deposition, Stowe testified that around “80% of his Emory salary ($187,000) comes from his NIH grants,” the letter notes. His total Emory salary was $232,000.

In a June 11, 2008 statement on the Senate Floor, in describing his investigation, Grassley said, “I have been looking at how drug companies try and influence medical care in America. Companies can do this by, for example, creating studies favorable to their drugs, by hiring doctors to promote their products, and in some cases even intimidating critics of their drugs.”

On this date, Grassley was announcing his investigation of Glaxo regarding revelations in reports filed in Paxil suicide litigation by Dr Joseph Glenmullen, showing the company had manipulated the numbers on adverse events related to suicidality in clinical trials all the way back in 1989, before the drug was FDA approved, to make it appear that Paxil did not increase the risk of suicidal behavior when, in fact, trial subjects on Paxil were eight times more likely to attempt or commit suicide than patients taking a placebo.

“So what did GlaxoSmithKline do with these reports?” Grassley said. “Well, the company tried to hide them.”

“They went to the judge and asked to have Dr. Glenmullen’s report and all the confirming documents placed under seal-that means that no member of the public could see them,” he said. “In fact, Glaxo has been doing everything possible to ensure that this information remains under court seal.”

“It seems to me that GlaxoSmithKline tried to hide these reports because they seem to demonstrate what the company knew-that Paxil was associated with an increased risk of suicide based on the company’s own studies,” Grassley noted.

“Essentially, it looks like GlaxoSmithKline bamboozled the FDA,” he pointed out.

For easy reference, psychiatric academics identified by Grassley’s investigation to date, as not fully disclosing money from drug companies, include Joseph Biederman, Thomas Spencer and Timothy Wilens at Harvard, Charles Nemeroff and Zackery Stowe from Emory; Melissa DelBello at the University of Cincinnati; Alan Schatzberg, president of the American Psychiatric Association, from Stanford; Martin Keller at Brown University; Karen Wagner and A John Rush from the University of Texas; and Fred Goodwin, the former host of the radio show, “Infinite Minds,” broadcast for years by National Pubic Radio, before it was thrown off the air.

Paxil All-Star Team

During direct examination of Healy, Tracey introduced an exhibit on a 2002 forum called, “Perspectives on Psychiatry for the Future, Summary of Program Evaluations,” along with a list of doctors who gave presentations.

“What I would like to do is use this document to prove that these are a list of doctors that are out promoting Paxil for the defendant, and to have Dr. Healy explain, as he has published, how GSK sought to change the culture of how doctors view Paroxetine and pregnancy,” he told the judge.

Tracey went through several of the presentations and named off doctors that included Daniel Christensen, Zachary Stowe, Philip Perera, Dean Hamer, Dwight Evans, Karen Wagner, Katherine Beebe, and Prakash Masand.

Healy said he believed that most of the doctors mentioned were on the Paxil speaking team.

Zachary Stowe was listed for a presentation on the topic of, “Use of Antidepressants in Pregnant and Breastfeeding Women.”

Page 10 of the document asked: “As a result of the program, what changes, if any, will you make in your practice?”

Healy testified that after talks at this type of program, the audience will be asked to rate the points that are made. Tracey read some of the comments made by doctors attending the seminar, which included: “Possibly less fearful of treating pregnant women,” “Increased comfort in treating pregnant women,” “Increase use of Paxil – Will reassess the use or nonuse of SSRIs in pregnant/lactating clients,” and “More aggressive in treatment of special population, children and pregnant women.”

Healy testified that this document supported his opinion that Glaxo did influence doctors’ prescribing practices with respect to Paxil and pregnancy and “they were quite successful at this.”

“I don’t think you can find a single comment which says, I will be more cautious about treating pregnant women with Paxil,” he pointed out.

The jury was also shown a “Protocol” where Stowe had applied to Glaxo for funds to do research on the issue of Paxil in breast milk. Under the objectives for performing the study, there were five possible boxes to check, and Glaxo checked the box for “image enhancement.”

Healy knew of no article that ever appeared in peer-reviewed literature or was published in a reputable journal where the author said the purpose of the study was image enhancement. The odds of getting a paper published in a leading journal “would be remote to nonexistent,” if you told the journal that the reason for the study was to enhance the image of the drug, he said.

Tracey then introduced a January 10, 2000 email from Jillian, at the Cohn and Wolfe PR firm, to Scott Sproull and others at Glaxo, that showed Stowe was going on a publicity tour and would issue a press release for the Paxil breast milk study on Emory letterhead to lend credibility to the study in the media.

The email stated: “Scott, please review the attached press release and forward me any comments or edits.”

“As you may know,” Jillian said, “Dr. Stowe is on board for publicity efforts and Sherrie and I are coordinating time to meet with him next week to arm him with key messages for this announcement, which is slated for February.”

“We are sending the release for his review at the same time in efforts to secure distribution on Emory letterhead,” the email said, “as you know would provide further credibility to data for media.”

Healy had never hired PR firms to disseminate his published literature or lent his name to go on publicity tours for drug companies, he told the jury.

Tracy presented another protocol for a Paxil study, with Stowe as the investigator, where the objective checked was again “image enhancement.” As a scientist looking at the design of this protocol, Healy said, “this appears to be part of the positioning of Paxil as a drug that will be favorable to women of childbearing years.”

The budget for the study showed that Glaxo would pay $600 for each patient enrolled and the cost would be about $9,000.

Prior to 2005, Healy testified, he was not aware that Glaxo “spent any money to actually determine if the drug could be causing birth defects in human children.”

Tracey produced another document from a September seminar held in Philadelphia, at which Kimberly Yonkers was speaking to a Women’s Health Advisory Board. Healy said Yonkers was a professor of psychiatry from Yale University and she was on Glaxo’s Women’s Health Advisory Board.

He told the jury that Yonkers was particularly influential “from the point of view of issues to do with women’s mental health.”

Glaxo’s Speed Dial

During the trial, Tracey wanted to use an exhibit that he referred to as a “telephone book,” full of influential doctors on Glaxo’s speakers’ bureau for Paxil and have Healy go through some of the names.

“What I would like to do is put it into the record and have him identify who these people are,” Tracey explained to the judge in chambers, outside the hearing of the jury.

“Many of them are influential psychiatrists who have published on Paxil,” he said. “I want him to go through seven or eight names so later when the jury hears literature by these authors they will be able to put it into context.”

What I am going to do “is show the jury how all-encompassing their strategy for identifying and cultivating psychiatrists were in the country,” Tracey said.

“That’s part of Doctor Healy’s opinion,” he said, “how they identified these hundreds of doctors across the country to change the culture that existed.”

While Healy was testifying, Tracey introduced the 171 page list and had Healy identify some of the doctors.

Healy testified that Lori Altshuler is “a figure who is very well known in the field of women’s mental health and would have written some key articles on the idea that it may be appropriate to use antidepressant drugs for women who are pregnant.”

He identified Vivian Burt as “a person who is a fairly big name in the women’s mental health field and, again, a person who is an advocate for using antidepressants in women of childbearing years, and in particular, has talked regularly about the use of Paxil for women of childbearing years.”

He said Lee Cohen had been on the Paxil advisory board. “Dr. Cohen wrote an article that has since become quite famous,” he told the jury. “It became famous not because of the contents of the article, but because Dr. Cohen and co-authors, most of whom are on this list, failed to disclose the links to GSK or the other companies in the field that they had.”

Some of Cohen’s co-authors on this study titled, “Relapse of Major Depression During Pregnancy in Women Who Maintain or Discontinue Antidepressant Treatment,” included Lori Atshuler, Vivian Burt, Jeffrey Newport, Zachary Stowe, and Aadele Viguera.

On July 11, 2006, with the headline, “Financial Ties to Industry Cloud Major Depression Study,” the Wall Street Journal reported that, “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.”

Most of the authors, the Journal said, were psychiatrists at Harvard’s Massachusetts General Hospital, Emory University, and the University of California Los Angeles.

The Journal noted that Cohen was a longtime consultant to three antidepressant makers, a paid speaker for seven, and had research funded by four drug companies. Adele Viguera, associate director of the Mass General perinatal psychiatry program and professor at Harvard, failed to disclose a paid speaking relationship with Glaxo.

Lori Altshuler, director of the Mood Disorders Research Program at University of California Los Angeles, failed to disclose that she was a speaker or consultant for at least five antidepressant makers. “Two of her colleagues — Vivien Burt and Victoria Hendrick — were also authors who didn’t report financial relationships they have with antidepressant makers,” the Journal reported.

In an expert witness report for the Novak Paxil birth defect case, Dr Dee Mangin points out that: “The Cohen study was not a controlled study, used a highly selected population likely to have a high relapse rate and not representative of a primary care patient population.”

“In addition,” she said, “it is not clear that subjects had a tapered withdrawal, which would increase the likelihood of misclassification of withdrawal symptoms as relapse.”

Mangin reports that in the year the study was published, one KOL (with the name redacted), received $72,000 from Glaxo in the first 6 months of 2006 alone, for giving 28 talks, which works out to $2,880 per talk.

The next name on the list read to the jury was Katherine Wisner, “a figure who has published quite extensively on the issue of it being often quite good to treat women of childbearing years and even women who are actually pregnant with antidepressants,” Healy said.

“She puts forward the point of view that it may be more harmful to leave the condition untreated,” he told the jury.

Charles Nemeroff’s name was on page 110. “He was probably the leading figure in the field or the leading person on this list,” Healy said.

Zachary Stowe was on page 151, and last name read was Kimberly Yonkers. Healy called her “extremely influential.”

Convenient Report Appears

During cross-examination, Varner asked Healy about a report that was co-published in the journals, Obstetrics and Gynecology and General Hospital Psychiatry, in September 2009, the very month that the first Paxil birth defect trial was scheduled to start, which she claimed was a joint statement from the American Psychiatric Association and the American College of Obstetrics and Gynecology.

The report was titled, “The Management of Depression During Pregnancy.”

“The purpose of this deliberation,” Varner said to Healy, “was to come up with a statement from those two organizations that would assist prescribers in making their decisions about how to treat depression in pregnant women, correct?”

“We do not know that this was endorsed by APA,” Healy said. “We don’t know if it was endorsed by ACOG.”

“We don’t know whether it was a collection of individuals who just got together and because they belonged to both APA and ACOG, thought that they could put this kind of title on the piece,” he told the jury.

“It’s correct, is it not,” Varner asked Healy, “that ACOG and APA describe some of the risks that were found (with SSRIs) that were, quote, extremely small and not replicated by other studies?”

“It’s not correct to say that at all,” Healy said. “APA and ACOG have not said this.”

“What you got is a number of authors here who are linked to either APA or ACOG who have said this,” he told Varner. “The reason that I make this point is I have been party to processes like this on behalf of the British Association for Psychopharmacology and I can tell you exactly, if you want, how statements like this arise.”

“I’m not asking that,” Varner stated, cutting Healy off.

In fact, during the trial, the jury saw a January 2009 paper published in the ACOG Journal, by authors from Yale, in which Paxil was number two on a list of commonly prescribed “teratogenic” drugs.

It should also be noted that in 2006, about 30% of the American Psychiatric Association’s $62.5 million in financing, came from the pharmaceutical industry, which means the group received close to $19 million from drug companies in 2006 alone.

During Healy’s testimony, Varner read a portion of the study that stated: “While some linked database reports find that compared to unexposed offspring, those exposed to Paroxetine during the first trimester are at higher risk. These results are disputed by other reports including several large case cohort studies.”

The actual study lists citations to papers that supposedly support this statement, which included papers by Louik and Alwan. On redirect, Tracey asked Healy: “Do those two papers stand for that proposition?”

“No, they don’t,” Healy said. “They both show an increase in risk with Paxil.”

Tracey pointed out that this study “curiously enough came out this month.”

“It did,” Healy said. “This was quite curious in its own right.”

They then went over the names of some of the authors that were not read during Varner’s questioning. Authors one and two were Kimberly Yonkers and Katherine Wisner. Healy testified that Yonkers and Wisner are affiliated with Glaxo and Yonkers was part of the women’s health advisory board for Paxil. “They have been strongly associated with efforts to change the cultures,” he told the jury.

The disclosures for the study showed Wisner was on the speaker’s board of Glaxo and Yonkers had received a research grant from Eli Lilly in the past year and had received a study drug from Pfizer for a National Institute of Mental Health trial.

Tracey noted that Glaxo was not mentioned in Yonkers’ disclosures. “It’s curiously not,” Healy said.

A likely explanation for Yonkers’ non-disclosure is that she is a member of the DSM-V Task Force and according to the conflict of interest statement on the Task Force website, “Yonkers has agreed that, for the calendar year 2007 and continuing for the duration of her work on the DSM-V Task Force, her aggregate annual income derived from industry sources (excluding unrestricted research grants) will not exceed $10,000 during any calendar year.”

Diana Dell and Nada Stotland, the past president of the APA, were also co-authors and online disclosures show them listed as members of Glaxo speaker’s bureau.

A website called “Bio-med Experts,” contains papers authored or co-authored by Yonkers. A “preview profile” lists Yonkers’ co-publications with Katherine Wisner, Viguera Adele, Lori Altshuler, Diana Dell, Nata Stotland and a total of five with Lee Cohen.

She also co-authored 12 papers with Martin Keller, six with John Rush, and several with Allen Schatzberg and Zachary Stowe, all of whom were exposed by Grassley’s investigation as not properly disclosing all of their financial benefits from drug companies.

Throughout the trial, Glaxo maintained that it did not market Paxil to women of childbearing years or pregnant women. In fact, in her opening statement, Varner told the jury: “You will hear from that chair the folks who made the marketing decisions at GSK.”

“They will tell you that GSK did not, repeat, did not target pregnant women, did not target women of childbearing age,” she said.

Yet, in a 2003 supplement titled, “Special Issues Related to the Treatment of Depression in Women,” for the Journal of Clinical Psychiatry, Yonkers published an article derived from the teleconference, “Treating Depression: New Choices for a Chronic Problem,” supported by an unrestricted educational grant from Glaxo, which promoted the use of SSRIs by women from youth to old age.

In the conclusion section, Yonkers wrote, “SRIs (SSRIs) appear to be an efficacious treatment for women suffering from various depressive disorders throughout the life cycle. These agents have expanded treatment options for many women, especially women who experience intermittent symptoms such as with PMDD, and side effects of SRIs are typically less severe than those of TCAs.”

“SRIs appear to improve depressive symptoms in pregnant women and women suffering from postpartum depression, and they are a relatively safe option for breastfeeding mothers,” she said. “Additionally, their effectiveness appears to be enhanced by estrogen, making them a favorable treatment option for older women suffering from postmenopausal depression.”

In 2004, Yonkers, Cohen, and authors that included two Glaxo employees, published a paper in, “Psychosomatic Medicine,” on a study titled, “Paroxetine Controlled Release for Premenstrual Dysphoric Disorder: A Double-Blind, Placebo Controlled Trial.”

In the November 1, 2006 issue of “Journal of Women’s Health,” Yonkers, Cohen and others, published a paper titled, “Expert Guidelines for the Treatment of Severe PMS, PMDD, and Comorbidities: The Role of SSRIs.”

This work was supported by an educational grant-in-aid from Glaxo, the disclosure advised. “Several treatment modalities are beneficial in PMDD and severe PMS, but the selective serotonin reuptake inhibitors (SSRIs) have emerged as first-line therapy,” the abstract states.

“A burgeoning body of literature has emerged that supports the role of the SSRIs as first-line treatment of PMDD and severe PMS,” the authors wrote in the discussion section.

Back in December 2005, Yonkers was out doing damage control for Glaxo when the FDA changed the Paxil pregnancy category from C to D, and warned that, “studies in pregnant women (controlled or observational) have demonstrated a risk to the fetus,” and said the FDA “has determined that exposure to paroxetine in the first trimester of pregnancy may increase the risk for congenital malformations, particularly cardiac malformations.”

On December 14, 2005, the Washington Post wrote, Kim Yonkers “cautioned that the database studies that the FDA had used had limitations: Unlike controlled studies, Paxil may have been prescribed far more than other drugs, skewing the results.”

She also claimed the databases sometimes concealed unrelated medical problems that could alter outcomes, the Post reported.

“Depression is still undertreated,” Yonkers said. “Pregnant women in particular are immensely undertreated, and you worry about people being unduly frightened.”

Yonkers’ September, 2009 report noted that in 2003, approximately 13% of pregnant women took an antidepressant sometime during their pregnancy. There are over 4 million babies born each year in the US, according to the CDC, which means about 520,000 pregnant women took antidepressants in 2003, and that would only cover live births. There is no telling how many infants may have died before birth, as a result of their mother’s use of SSRIs.

In 2006, Yonkers became president of the North American Society for Psychosocial Obstetrics and Gynecology, after Diana Dell turned the job down. The April 2006 Spring Newsletter discussed this group’s annual meeting, held in Hawaii no less. “The symposia at our 33rd Annual Meeting were fabulous, and we all appreciated the luxurious hotel and beautiful Big Island’s many charms,” the newsletter stated.

“Kim Yonkers’ unending drive, and with significant assistance from Meir Steiner and Claudio Soars culminated in our Sponsors contributing generously towards the symposia,” it said. The sponsors listed included the drug companies Berlex, Sepracor, and Wyeth.

Although the judge ruled that Healy could not elaborate on the Nemeroff and Stowe saga, during cross-examination, Varner opened the door a crack by directly asking Healy about the reputations of the various doctors shown to be on Glaxo’s payroll.

“The last question I have about the documents that you reviewed with Mr. Tracey yesterday goes to the portion of your testimony when you and Mr. Tracey talked about various doctors who had received honoraria from GSK for various speaking engagements,” she said.

“And you listed Doctor Altshuler, Doctor Wisner, Doctor Burt, Doctor Yonkers, Doctor Cohen, Doctor Nemeroff, Doctor Stowe, and Doctor Szuba,” she pointed out.

“They are generally respected in the medical community?,” she asked Healy.

“The issue of the degree of respect within the medical community is one that’s open to question at the moment,” Healy said.

“It would be interesting to know what the degree of respect for Doctor Nemeroff or Doctor Stowe in the medical community is at the moment,” he added.

The latest news on Nemeroff came on January 4, 2010, when Pharmalot carried the headline: “Charles Nemeroff and the House That Glaxo Built?”, and Ed Silverman wrote, “the controversial psychiatry professor who became a subject of a US Senate Finance Committee inquiry into academic research and pharma industry influence, is joining the University of Miami’s Miller School of Medicine.”

“Of course, this means leaving his previous job at Emory University in Atlanta and so he’s just purchased a $1.9 million house in the Coconut Grove section of Miami,” Silverman said. “The 5,204-square-foot home has six bedrooms and seven bathrooms,” according BlockShopper.

Nemeroff “came to the Senate committee’s attention because he was accepting sizeable consulting fees from Glaxo at the same that he was the primary investigator on an NIH-funded grant for research into a Glaxo drug,” he pointed out.

“In any event,” Silverman wrote, “the new home appears big enough to house plenty of consulting materials.”

Amazingly, none of the KOLs or advisory panel members on Glaxo’s payroll discussed above, who are so “generally respected in the medical community,” according to Varner, were recruited to testify for Glaxo in the first birth defect trial.

Ghostbusting

Yonkers now works at Yale, but she received her medical training at the Columbia College of Physicians and Surgeons, and completed a residency and fellowship at McLean Hospital, Harvard Medical School. Lee Cohen and Adele Viguera are still at Harvard.

The month after the trial ended, in November 2009, Grassley sent letters to ten medical schools asking them to describe their policies on plagiarism and ghostwriting and to identify any complaints or investigations of faculty members dating back to 2004. The Universities included Columbia, Yale, Harvard, Duke, Stanford, Johns Hopkins, University of Pennsylvania, Washington University, University of California at San Francisco, and University of Washington.

“Essentially, the companies are using the reputation of prestigious academic researchers and their institutions to promote the sale of drugs and devices,” Grassley said in the letters.

“Articles published in medical journals are widely read by practitioners and are relied upon as being objective and scientific in nature,” he wrote. “The information in these articles can have a significant impact on doctors’ prescribing behavior and, in turn, on the American taxpayer, as the Medicare and Medicaid programs pay billions of dollars for prescription drugs and medical devices. “

“Any attempt to manipulate the scientific literature, which can in turn mislead doctors to prescribe treatments that may be ineffective and/or cause harm to their patients, is very troubling,” Grassley said.

“Students are disciplined for not acknowledging that a paper they turned in was written by somebody else,” Grassley said. “But what happens when researchers at the same university publish medical studies without acknowledging that they were written by somebody else?”

Back July 2009, Grassley asked eight medical journals to describe their policies and practices regarding ghostwriting. “Articles published in medical journals are widely read by practitioners and are relied upon as being objective and scientific in nature,” he said in letters to the journals. “Concerns have been raised, however, that some medical literature may be little more than subtle advertisements rather than independent research.”

On January 3, 2010, the New York Times ran the headline: “Harvard Teaching Hospitals Cap Outside Pay”.

“Senior officials at the two hospitals, Massachusetts General and Brigham and Women’s Hospitals in Boston, must limit their pay for serving as outside directors to what the policy calls “a level befitting an academic role” — no more than $5,000 a day for actual work for the board,” reporter Duff Wilson wrote.

“Some had been receiving more than $200,000 a year,” he said. “Also, they may no longer accept stock. “

As an example, the Times noted that Dr Daniel Podolsky was the original chairman of the Partners policy commission in 2007, when “he was the chief academic officer at Partners and a $191,000-a-year board member at GlaxoSmithKline.”

Partners HealthCare is also forbidding speaker’s fees from drug companies for any employee, “including nearly 8,000 with Harvard faculty appointments,” the Times reported.

(The Paxil Birth Defect Litigation Update Series is sponsored by the Houston law firm of Vickery, Waldner and Mallia at http://www.justiceseekers.com)

Filed under: 2010, Birth Defects, ghostwritten, Glaxo, Kilker, KOL, Paxil, Paxil birth defect litigation, SSRIs, Vickery

Battle of the Experts – Paxil Birth Defect Litigation

Evelyn Pringle February 22, 2010

In the first Paxil birth defect trial that resulted in a $2.5 million verdict against GlaxoSmithKline, the infant, Lyam Kilker, was born with three heart defects; an atrial septal defect, a ventricular septal defect, and an interrupted aortic arch, after his mother took Paxil while pregnant.

Pregnant women cannot participate in clinical trials on drugs due to the risk of harm to the fetus. But after a drug has been on the market for a while, epidemiology studies can review the medical records of women who have taken a new drug while pregnant and the records of women who were not exposed to the drug while pregnant and compare the outcomes of the infants.

The plaintiff’s experts, Doctors Ra-id Abdulla, David Healy, Shira Kramer and Suzanne Parisian, all testified that they believed Paxil (paroxetine) caused Lyam’s defects, based in part, on the scientific literature on studies available on Paxil to date.

Battle of the Experts

During her opening statement, Glaxo’s lead attorney, Chilton Varner, told the jury, the “experts in the case diverge sharply on how they interpret that body of scientific literature.”

The “plaintiffs’ experts say that these scientific studies prove causation, they prove that Paxil causes cardiac defects and IAA,” she noted.

“They get there by … lumping all cardiac defects together and looking at the numbers for cardiac defects as a group,” she said, “They also get there by rejecting any application of the tool of statistical significance.”

“The plaintiffs’ experts will tell you they believe that as long as there is a difference between the two groups, and the Paxil group is higher than the control group, that’s enough,” Varner told the jury.

“GSK’s experts, on the other hand, are anti-lumping,” she said. “They say that you can’t lump all heart defects together because they form for different reasons at different times by different processes and that you can’t use evidence as to one kind of defect to imply that it also applies to another kind of cardiac defect.”

“And GSK’s experts will tell you that statistical significance matters,” she stated, “that without applying the tool of statistical significance, you have no idea whether the difference between the two groups is real and meaningful or whether it is simply the operation of chance or coincidence.”

Dr Shira Kramer, an epidemiologist, testified as an expert for the plaintiffs and explained epidemiology studies to the jury. She described the difference between association and causation as meaning that a single study with a finding of an elevated risk of birth defects would only show an association.

“When you have a body of literature which shows through multiple studies consistently elevated findings, then you move from association in one study to causation, that this factor causes the disease,” she told the jury.

During closing arguments, the family’s lead attorney, Sean Tracey, told the jury that, “Defense lawyers can’t stand the word ‘causal.’”

“Causal” is the “kiss of death” for a defense lawyer, he said, because they know that is one of the questions the jury will be asked.

“The second question you are going to be asked,” he told the jury, is “Do you find that Michelle David’s ingestion of defendant’s drug Paxil was a factual cause in bringing about the heart defects?”

While testifying, Kramer also explained what is meant by relative risks and confidence intervals. “Our real interest in epidemiology is to measure rates of disease and excess risk,” she said. “But we also want to know really how precise is this measure.”

“And the precision of this measure is very much tied to the size of the population that you are studying and the number of exposed people,” she explained.

“In other words,” she said, “if we were to go into a large population and do the same study a hundred times, how many times out of a hundred would we find the same exact answer?”

“It is similar to tossing a coin,” she noted. ”If you are looking at the proportion of heads and tails in a coin toss, and you toss that coin a thousand times … you are going to come up with that 50/50 proportion pretty much all the time.”

“That’s a very precise answer,” she pointed out.

“So if you think about it that way,” Kramer said, “the larger the sample size, the larger the number of people that you study, the more precise your study estimate of that relative risk is.”

“And we estimate the precision of this relative risk by calculating something called confidence interval,” she told the jury. “If you were to repeat this study, let’s say 95 times out of a hundred, what would that range be?”

For instance, where the relative risk in a study is 2, and they calculate statistically a 95 percent confidence interval with a range of between 1.5 and 2.5, the actual relative risk would fall somewhere in this range. That “means 95 trials out of a hundred would generate results in this range,” Kramer stated.

A test that is not statistically significant should not be discarded, she said. The “practice of statistical significance testing has been very much rejected in epidemiology because it was never developed really to study health or biomedical or human health problems.”

“This whole issue of rejection of a hypothesis, yes-no answers,” she explained, “was created for agricultural and industrial studies, whether or not a certain widget would be produced more efficiently in one production method than another or whether one field is more productive than another in an agricultural setting, these are easy yes-no answers and don’t impact human health.”

“But, unfortunately,” she said, “it was for a long time memorialized into epidemiological practice because it was easy and because before computers, these statistical tables were published, it was just easy to look up these probability values, it was easy to say, oh, yes, oh, no, to statistical answers”

“But, in fact, they don’t take account of the importance and the toll on human health,” Kramer told the jury.

A single-minded focus on significance testing is dangerous from a public health perspective, she said, because “it leads to discarding very important and relevant data and studies.”

Studies Designed to Fail

During his opening statement, Tracey told the jury: “You are going to hear from experts in this case that there are ways to design studies to fail.”

“If you truly don’t want to know the truth,” he said, “very smart people can design studies that won’t show you the truth.”

While testifying, in regard to studies, Kramer was asked to explain what is meant by “inclusive by design.” It’s “a very, very serious problem that has been written about quite a bit,” she told the jury.

The reason for “the tremendous amount of concern and literature on this topic,” she said, “is many of these studies look like they have been designed to fail.”

It’s the “deliberate design of epidemiological studies in such a way as to make it, if not impossible, extraordinarily difficult to detect relationship between an exposure and an outcome or a disease,” Kramer explained.

“It’s to design in or not to design in certain features of a study which would make it almost impossible to find the information that one is seeking,” she added.

In the Paxil studies, many of the “designed characteristics have been such that they would minimize or make it more difficult to detect an increased risk,” she said. “And despite that, these studies have shown consistency in showing an increased risk of cardiac malformations associated with first trimester Paroxetine exposure.”

This is what “is so compelling about these studies,” she told the jury, “despite the fact that just about every aspect of these studies would tend to drive that relative risk down or make it difficult to detect an elevated risk, we are seeing them study after study after study.”

“The pressure is always against the ability to detect increased risk in the way these studies are designed,” Kramer said. “And, yet, despite that, we are seeing consistently elevated risks associated with Paxil, which is very, very important, very compelling, and very alarming actually.”

Whether a study will be inclusive by design is decided by the researchers conducting and authoring the study, she said.

Kramer explained that a “meta-analysis is an analysis of all the data that have been generated on a subject, so it’s an agglomeration, a statistical analysis of all the data to come up with a summary risk for all of the studies together.”

“It’s an attempt to overcome the issue of small sample sizes,” she said, “so the individual doing the meta-analysis will take all of the studies and will actually combine all of the results into summary statistics so that there is more power and there is some attempt to come up with a summary of all of the data that have been generated to date.”

Glaxo’s Meta-Analysis

The famous neuropsychopharmacology expert from Wales, Dr David Healy, also testified for the plaintiffs. During his testimony, the jury was presented with two charts from Glaxo’s own website, showing the results of its own internal meta-analysis of the existing epidemiological studies.

The analysis had only been put on the website recently, he noted, maybe last year. One chart showed all birth defects lumped together, or combined, and the other showed cardiac birth defects.

In discussing the chart on combined birth defects, Healy said, “what everybody here needs to see is … the little dots in the middle of the lines.”

If you “look at the pattern of dots there, you will see that of all the studies that have now been done, most of the dots fall on the right-hand side,” he noted. “This means that there is an increased risk that Paxil causes birth defects.”

“What I want you to look at here … is the consistency,” he told the jury. “The dots are all falling on the right-hand side of the line, which shows an increased risk.”

“When GlaxoSmithKline added all this up,” Healy said, “you see the dot at the bottom, that is statistically significant.”

“They say there is no chance that Paxil is not causing these birth defects. Chance is gone. It is causing the birth defects,” he told the jury.

With the chart on cardiac birth defects, “again, you see the patterns of dots are mostly on the right,” Healy pointed out.

“What you see here at the end,” he said, “shows you a 1.5-fold increase in risk.”

This “comes from their Web site,” he stated, “I have had no part in trying to generate these data at all.”

While testifying, Healy discussed several of the studies in Glaxo’s analysis, including the abstract for a presentation given at a conference in 2001, referred to as Unfred, which also had an author named Chambers. The full paper on the study, with Chambers as the author, had never been published but the data from the study was in Glaxo’s database.

“These data almost 10 years later,” Healy said, “showing a fivefold increased risk in heart defects and a tenfold increased risk in birth defects in general has not been published.”

Second Expert

During her testimony, Kramer also went over Glaxo’s meta-analysis and explained what it showed.

“GSK determined that the odds ratio for cardiac malformation as a broad class was 1.48,” she told the jury. “That is a 48-percent increased risk where they have combined data from all of the studies that they could find to date.”

“They also found an odds ratio of 1.67 for septal defects,” she said. “That is a 67-percent increased risk of septal defects associated with first trimester Paroxetine exposure for all the studies, for the three studies where there was actually data on septal defects.”

“And then for their summary odds ratio for right ventricular outflow tract obstruction defects,” she added, “the two case control studies which actually looked at those types of defects they found a summary odds ratio of 2.85.”

Most of the studies in the meta-analysis did not break down the cardiac defects into subcategories, Kramer said. “Either because they simply didn’t have enough individuals in their studies or they set up their study rules which preclude them from doing so.”

It would be inappropriate to conclude that if a specific cardiac defect was not found in these studies that Paxil did not cause it, she said. “It would be very much inappropriate and erroneous to assume that because that subcategory is not mentioned … that there is no increased risk associated with it.”

Kramer also testified about the Wurst study, which was published only 12 or 13 days before she testified. The “GlaxoSmithKline meta-analysis that we just discussed was not published,” she told the jury. The “Wurst study is the published version … but updated with one additional study.”

She was asked whether there was anything new, novel or different in the Wurst study. “Well, the only thing that is different in … the published version versus unpublished version,” she said, “is that they did not publish any subgroupings of cardiac abnormalities, birth defects in the published version.”

They only “analyzed and published the summary odds ratio for all cardiac birth defects combined,” she noted.

“And that summary odds ratio was very similar to the first one,” she said. “It’s 1.46. That is a 46-percent increased risk for all cardiac defects combined.”

During cross-examination, Glaxo attorney, Todd Davis, told Kramer, “despite every single one of those studies looking at that those different patient populations over different time periods, there is not a single case in any of the studies that you talked about … that identifies a patient who was exposed to Paroxetine or Paxil who had an IAA …”

He noted that Lyam “was diagnosed with an interrupted aortic arch Type A,” and asked Kramer: “Can you — can you point to the jury in your report where you mention anything about interrupted aortic arch of any kind?”

“I probably didn’t because there is no specific study that analyzed that specific defect as a stand alone category,” she replied.

Kramer pointed out that “the epidemiological studies that have been conducted never individually analyzed the rates of the risk of interrupted aortic arch Type A associated with first trimester Paxil exposure.”

Because it is so very rare, she said, it would be impossible to do given the required sample size of “something over a million” subjects in order to conduct such a study.

“And since no such study was ever done,” she told the jury, “you would not expect to find any specific study that would have been able to analyze interrupted aortic arch Type A as a specific subgroup.”

Most of the studies, she said, “just reported on all cardiac malformations as a group and even those that … did any kind of subgroup analysis restricted them to the most common subgroups.”

There were several studies where they restricted any analysis to subgroups where they had at least 200 women whose child suffered a specific birth defect, “which would automatically exclude IAA Type A,” she pointed out.

The Louik paper restricted the analysis to subgroups of 100, she said. But the “Louik study itself very clearly lists IAA as a specific cardiac malformation under conotruncal defects in their appendix where they list specific subgroups that they looked at and considered,” she told the jury.

Louik Study

The Louik study was funded by Glaxo and conducted out of the Slone Epidemiology Center For Birth Defects. While Kramer was testifying earlier, Tracey put up a slide entitled, “Louik, et al – GSK involvement,” and told her to tell “the jury what GSK’s involvement in this study was both publicly and then privately.”

Davis objected to this testimony. “There is nothing in Doctor Kramer’s expert report that discusses anything about communications with GSK that somehow impacted the Louik study, so there has been no notice to GSK that she would be offering those opinions today,” he argued to the judge, while the jury was out.

“Your Honor,” Tracey told the judge, “this issue is something that has been percolating for a number of years.”

“This information about GSK’s involvement and manipulation of the Louik study is something that has recently come to light,” Tracey said. “In fact, the deposition of their epidemiologist, Sara Ephross, was taken after Doctor Kramer’s, the deadline for Doctor Kramer’s report.”

“And, in fact, last week, while we were in trial,” he told the judge, “a Federal Court in Boston has ordered the Slone Epidemiology Center and GSK to turn over documents related to their involvement in this study.”

“Quite frankly,” he said, “the only people prejudiced by this are the plaintiffs, because GSK knows exactly what they did and when they did it, and we have been trying to get this information for some time.”

The judge excluded testimony by Kramer about the email exchange between Dr Loiuk and Ephross.

But the comments by Louik, not seen by the jury, that appeared in court filings, stated in part: “we did not accept your changes. We are trying to avoid reinforcing the widely held perception that ‘statistical significance’ is a standard by which to judge the validity of a study finding. Significance is a function of study size, and while a single non-significant result might not be credible, in this case it supports findings from other studies and should not be dismissed for reasons of significance alone.”

In affidavit filed in the Federal Court that ordered the release of the communications between Glaxo and the Slone Center, Louik wrote: “We rejected all of GSK’s suggestions that might have served to weaken our findings and conclusions.”

“GSK suggested that our ‘overall’ findings did not support the hypothesis that Paxil increases the risk of cardiac defects,” she stated. “We rejected that suggestion as well.”

Birth Defect Numbers Halt

In the beginning, when Paxil was approved in the US, although Glaxo did not list the number of birth defects cases reported on the label, if a doctor contacted the firm wanting information, Glaxo sent out medical information letters that included the number of birth defects reported.

Tracey entered three such letters into evidence. The first letter listed 36, the second 42, and the third 64. Then in the late 1990s, instead of including the number of birth defects, the medical information letters started only listing the percentages, and after that they went to listing nothing, Tracey told he jury in closing arguments. “It goes from numbers to percentages to nothing.”

During the trial, a Doctor Hobbiger testified that Glaxo enacted a policy not to give doctors the numbers because doctors were incapable of putting it into context. “The funny thing about that to me,” Tracey told the jury, “is why were the doctors capable of putting the numbers in context when the numbers were low?”

“How did they magically become incapable of rational thought once the numbers became high?,” he pointed out.

He noted that a big thing happened in1998. Glaxo analyzed all the data they had been receiving on Paxil, and the person writing the report made the following finding: “The number of reports we have of women with birth defects is an alarmingly high number. We should not see this number of birth defects. It’s four to five times what we would expect to see.”

“This is an internal document that nobody has ever seen before, not the FDA, not anyone,” he said.

Earlier in the trial, Tracey had showed the jury a letter from 1984, in which the FDA specifically told Glaxo they needed to tell the FDA “whether or not you receive any alarming information either in animal studies or in the human population.”

“And in1998 this is their language, not mine,” Tracy told the jury. “The incidence rate of congenital abnormalities as observed in data reported in this document is 13.3 percent.”

This is a problem, he said, because the background rate “is 2-1/2 to 4 percent, depending on who you believe.”

The 13.3 percent “is three to four times what they would expect to see,” Tracey point out.

Birth Defect Info Request Refused

During the trial, the jury learned that in May and June, 2001, Glaxo received two emails from a woman specifically asking for any information Glaxo might have on birth outcomes of babies born to mothers who took Paxil.

The woman reported that she had recently gotten married and immediately became pregnant because they wanted lots of children. But when she was six months along, the woman had to terminate the pregnancy after tests showed the baby had a rare heart defect and would likely not survive to term or survive the necessary open heart surgery to save his life if born alive.

“To say the least, I was absolutely distraught with this news,” the woman said. “I thought this was something that I did … because I stayed on the Paxil for selfish reasons.”

“I wanted to know if you could direct me to any information you might have of any woman that has taken Paxil and still had healthy babies,” the woman wrote, near the end of May 2001.

“My husband and I are ready to try again to get pregnant in the next month or two,” she said. “I am so nervous.”

The woman had been on Paxil for over four years and said she loved how the drug worked for panic attacks. “I don’t want to stop taking my miracle pill,” she wrote. “But, then again, if there is a chance that this might hurt or affect the baby, I want to know upfront.”

“And I will somehow stop taking it for the time being,” she added. “Please contact me as soon as possible. Please don’t forget about me.”

The woman sent a second email on June 1, 2001, and stated: “This response is in regards to an e-mail that I had sent you previously.”

“I was asking to see if you have any or are in the process of any clinical trials for women who are currently on Paxil and pregnant,” she said. “I wanted to find out information to see how many women were on Paxil during pregnancy and if they were able to successfully have healthy babies.”

“I love the product, and I don’t think I could have gotten through my panic attacks without the wonderful help of this miracle drug,” she told Glaxo.

“I just want to start to try and get pregnant again soon,” she wrote. “I do not want to put my unborn child through anything that would hurt him/her.”

“Please, if you do not have this information, where is this information held?” she wrote. “Does anyone do studies like this? Please, any information you may give me would be great.”

Glaxo wrote her back on June 6, 2001. “We are attaching a copy of our current product information for Paxil. Please review the section on use during pregnancy,” the letter read.

“Further questions about your treatment should be directed to the physician, pharmacist or healthcare provider who has the most complete information about your medical condition,” they said. “Because patient care is individualised, we encourage patients to direct questions about their medical condition and treatment to their physician.”

“We believe that because your physician knows your medical history, he or she is best suited to answer your questions,” Glaxo wrote. “Our drug information department is available to answer any questions your physician or pharmacist may have about our products.”

Glaxo sent the woman basically a form letter on June 13, 2001, asking for her signature on an authorization to get her medical records, but provided no answers to the woman’s questions.

On a Glaxo internal document with the same date, the box “almost certain” was checked for “Relatedness assessment to medication.” There is no higher category of certainty that the drug caused the defect than the box checked.

A Glaxo employee at the time, Jane Nieman, was listed as the contact person on a report sent to the FDA. Before trial, Tracey took Neiman’s deposition and questioned her about Glaxo’s policy for reviewing adverse event reports prior to showing her the documents about the mother who aborted her baby that said it was “almost certain” that Paxil caused the heart defect.

Portions of the deposition were played for the jury. Before Nieman knew about the documents, she testified that when a causality assessment was made a physician was involved and it was a team effort. “I think it is very much a team,” she said. “I think that’s really how they worked.“

“They would look at the case and they would form a medical opinion as to whether there was a possible, probable or no causality,” she stated.

Tracey told the jury that Nieman was “stunned” when she saw the document with the box checked, “almost certain,” so he asked her whether she was uncomfortable with the fact that the assessment was made. “It was made. It’s a fact,” she said in the deposition. “I don’t feel uncomfortable with it.”

Later in the deposition, Nieman claimed she did not know who checked that box. “Somebody from GSK filled that in,” she said. “There’s a possibility someone made a mistake and checked the box wrong.”

During the trial, Glaxo had Doctors, Stephen Hobbiger and Judith Jones, tell the jury that the checked box was definitely a mistake because they don’t do causality assessments in the US citing “almost certain,” that they only do it that way in France.

During cross-examination, Tracey showed Jones a causality assessment from Canada that had “almost certain,” and she said well, maybe they do it that way in Canada. He then showed her one from the US that also had “almost certain.”

In the documents sent to the FDA, Glaxo did not include the words “almost certain,” according to testimony by Dr Suzanne Parisian, a former FDA official.

Parisian said Glaxo also never changed the Paxil label after receiving the report and the rules are that a drug company has to change or strengthen the warning on the label, if “they have reasonable evidence of an association with the report for their product and an adverse experience.”

Smoke and Mirrors

“The bottom line of the scientific evidence that will come to you from GSK’s experts will be that there is no way based on the current state of the scientific evidence to state to a reasonable degree of medical certainty that Paxil causes birth defects in general or causes cardiac defects in general or causes Lyam Kilker’s specific defect of an IAA,” Varner told the jury during her opening statement.

Throughout the trial, Glaxo attorneys focused on Lyam’s IAA defect and harped on about “statistical significance,” when as described above, the studies were designed to ensure that a “statistically significant” increased risk in rare cardiac defects would never be detected.

During closing arguments, Tracey told the jury he wanted to talk about Glaxo’s “obsession” with ignoring the fact that Lyam had three cardiac defects.

“All they want to talk about is this interrupted aortic arch,” he pointed out.

“The reason is very clear,” Tracey said. “It’s because they know it’s rare.”

The “reason that they want to talk about it so much is because they know this, they’re never going to look for this,” he told the jury.

“They’re never going to do a study looking for interrupted aortic arch,” he pointed out.

“The only ones that would have the money, time and effort to undertake a study of 1.5 million women would be them,” Tracey said. “And they know it’s never going to get done.”

“So they’re in a can’t lose position if you buy their argument,” he told the jury.

The study is “never going to get done because they’re the only people that would do it and they’re not going to,” he said.

“They admit, though,” he pointed out, “that they have two cases now in their own database of interrupted aortic arch.”

During closing arguments, Tracey recounted how he had put up Glaxo’s own meta-analysis from the company’s website, with 9 different studies, including their own, and “each and every one of them says Paxil increases the risk of heart defects,” he pointed out.

“And this is a document that I know pains them,” Tracey said. “Because … the author of their own meta-analysis, Charlie Poole, the author that they hired …, when he looked at the data privately, privately, outside of courtrooms, he said: This begs the key question. Do we think the best explanation at present is that first trimester paroxetine use increases the birth prevalence of cardiac malformations? I do.”

“I do,” Poole said. “Outside the courtroom,” Tracey told the jury.

“But when this document got published, by the time it went through everybody’s hands, by the time the editing was over, that statement disappears,” he said. “It is not in the peer-reviewed literature.”

In her closing, Varner told the jury, “the final fact that matters is that no regulatory agency or medical organization has ever concluded or said that Paxil causes birth defects. Only plaintiffs’ experts have said so and in this courtroom,” she said.

In his final summation, Tracy said, “I want to put something to bed that Ms. Varner said immediately, and that’s this: Ms. Varner said that no regulatory agency in the world has ever said Paxil is a teratogen.”

“That is simply untrue,” he told the jury. “This is what the FDA says right here, There is positive evidence of human fetal risk,” reading from a letter from the FDA.

He also noted that Paxil’s label, under “Teratogenic Effects” states: ”Epidemiological studies have shown that infants exposed to first trimester exposure to paroxetine have an increased risk of congenital malformations, particularly heart defects.”

(The Paxil Birth Defect Litigation Update Series is sponsored by the Houston law firm of Vickery, Waldner and Mallia at http://www.justiceseekers.com)

Filed under: 2010, Birth Defects, Glaxo, Kilker, Paxil, Paxil birth defect litigation, pregnant, Vickery

Donate: Stop Preventable Infant Deaths and Birth Defects

Click here to lend your support to: Stop Preventable Infant Deaths and Birth Defects and make a donation at www.pledgie.com !

Be a Facebook Fan!

UNITE FOR LIFE Fan Page

UNITE FOR LIFE Fan Page

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

Join 729 other followers

Get the latest from the Fiddaman blog

Archives

UNITE News

September 2014
M T W T F S S
« Aug    
1234567
891011121314
15161718192021
22232425262728
2930  

Where Do People See This Blog?

Protect babies from drugs

Eli Lilly Funds Depression Screening Initiatives

depredrugshirt

Matthew Schultz killed by Effexor. Two hours old.

More Photos

Big Pharma Victim

  • I haven't been on in awhile thanks to all those who followed 3 years ago
  • @LindsayRush yay IOWA! 4 years ago
  • Another rainy day here in IOWA. Well at least i had a good time swimmin yesterday. 4 years ago
  • Hey everyone hope you have a great day! THanks to all the new followers :) and for those that continue to follow 4 years ago
  • srry if I dont get on here much I mostly just look at my facebook acct. thanks to all the new followers! 4 years ago

The Indiana Star

Christiane Schultz

  • Is not coping well at all. Loss sucks! 4 years ago
  • is scared to bond with this baby, just in case. 5 years ago
  • Happy 6 months today baby. I love you Matthew. 5 years ago
  • Living with loss, sucks. 5 years ago
  • Thinking I need to discuss plans for this baby soon or I will be having it in my doctors office. Where do I deliver? 5 years ago

Amery Schultz

Seeking Parents in Missouri for Celexa / Lexapro Class Action – Call 800-827-0087

TWEET FOR LIFE

BREATH – The Official Blog of MADNAP – momsandmeds.com

RSS BREATH

  • Untitled
    Originally posted on The Bitter Pill:Kickstarter is a website for artists to use to raise money and complete awesome projects. The best thing to come to the informed consent movement since Thomas Szasz could just be the new, upcoming film by Dan Jenski, “ADDicted” which basically gives Ritalin, Adderall, Concerta and the like a…
  • Untitled
    Originally posted on The Bitter Pill:In the studies submitted to the FDA for approving Zoloft (a drug that has killed numerous families, babies, mothers, children), the drug maker covered up the fact that Zoloft failed to outperform placebo, according to a new consumer fraud lawsuit filed by the firms Baum, Hedlund Aristei & Goldman…
  • Antidepressants Again Linked to Preterm Birth & Seizures
    In what was more than likely originally an attempt to prove that depression causes birth complications, researchers from Yale, Tufts, et al found in two new studies that antidepressants increase the risk of preterm birth and seizures. Read more at this link on the newly redesigned UNITE website.
  • Who Could Do This On Purpose
    Read this blog to find out
  • Canadian Regulation on Fetal Exposure to Psychotropic Drugs – Public Input Needed
    Canadian Regulation on Fetal Exposure to Psychotropic Drugs – Public Input Needed (Cross-Posted on The Bitter Pill blog) Amery and Christiane Schultz have been asked to provide input on proposed recommendations regarding psychotropic drugs in pregnancy in Canada. Amery & Christiane are hard-working activists affiliated with UNITE and MADNAP. Please send […]

UNITE ARCHIVES – Victims & Survivors Against The MOTHERS Act: YouTube Playlist

Videos: Psych Drugs, Birth Defects, Infant Death, Violence & Suicide

UNITE ARCHIVES – Add Your Group To The Coalition Against The MOTHERS Act

CADIMA: 54 Groups and Counting!

UNITE ARCHIVES – The MOTHERS Act Citizen Voting Area on Open Congress

Status: 76% AGAINST S. 324 The MOTHERS Act. Vote & Comment.

UNITE ARCHIVES – Join the Coalition Against The MOTHERS Act on Facebook!

3,271 Facebook Members and Counting!

UNITE ARCHIVES – Stop The Dangerous and Invasive MOTHERS Act!

13,500 Signatures and Counting!

Follow

Get every new post delivered to your Inbox.

Join 729 other followers

%d bloggers like this: