What this article fails to mention is that in the original Paroxetine (Paxil/Seroxat) clinical trials done by Glaxo it indicated that baby rat pups were dying when their pregnant mothers were fed paroxetine…
Yet despite this knowledge- Glaxo marketed Paxil/Seroxat directly to pregnant mothers regardless.
‘Attempted Corporate Manslaughter’ is the phrase I would use here..
If you take prescription medications, what conditions do you take them for? Are they working for you? Have you experienced any negative side-effects from them?
It may surprise you to know that answers to these critical health questions aren’t well-documented for most Canadians. Yet the answers would provide the crucial information needed to ensure our medications are safe and worth taking after they’ve been approved for use.
Before prescription drugs are approved in Canada, they’re tested under controlled conditions on relatively small numbers of patients (several hundred to several thousand) with selective characteristics (patients of certain ages, races, ethnic groups or genders). But once medications are approved, they aren’t monitored as closely as they should be.
We need to significantly improve our system of post-market surveillance for prescription drugs in Canada to make sure we are continually monitoring their safety and effectiveness in real-world settings.
First, adverse drug reactions may surface that weren’t previously detected in smaller pre-regulatory trials. Recall the unfortunate case of 15-year-old Vanessa Young. who was taking cisapride for her gastrointestinal symptoms and died after suffering a heart arrhythmia — a life-threatening side-effect of the drug that surfaced only after it was released onto the market.
Second, the use of a drug may broaden over time to include milder forms of the disease or even different medical conditions that weren’t assessed during the drug’s pre-market trials. Take antidepressants, for example. These medications are being increasingly used for conditions other than depression. New research has found that nearly one in three antidepressant prescriptions are written for unapproved (“off-label”) conditions — most of which aren’t backed by sufficient evidence.
To adequately monitor the safety and effectiveness of medications in real-world settings, we need a timely, post-market, drug-surveillance system that can identify the reasons why patients are taking their medications and follow patients to detect adverse drug reactions and determine if their medications are working.
How are we doing so far? Not great.
Identifying the reason for drug use
The medical reasons for prescriptions aren’t often explicitly documented in patient charts, nor is this information required for patients to fill prescriptions or receive reimbursement for drugs. So, when it comes to drugs like antidepressants that can be prescribed for different medical conditions, not knowing why a patient is taking a drug creates major challenges for assessing the drug’s effectiveness and appropriateness of use (i.e., whether the use is backed by regulatory approval or scientific evidence).
Detecting adverse drug reactions
Canada’s Adverse Drug Reaction Reporting System has many flaws, including the fact that it relies upon voluntary reporting by physicians via a reporting process that is time-consuming and outside of routine procedures. In fact, it’s estimated that less than five per cent of all adverse drug reactions are reported to Health Canada.
Tracking medication effectiveness
Once drugs are released onto the market, their real-world effectiveness isn’t systematically monitored. It’s troubling to know that we currently have no large-scale mechanisms in place to track whether patients are experiencing the anticipated benefits from their medications.
So, what’s the solution?
We need a national, post-market, drug-surveillance system that mandates the systematic collection of data on the reasons for drug use, adverse drug reactions and effectiveness, and governs the use of health-information technologies to collect these data.
Health-information technologies offer the chance to seamlessly collect such data as part of the care process and even enhance patient care. For example, electronic prescribing systems could prompt physicians to record the reason for treatment when drugs are prescribed and alert doctors to potential prescribing errors or present alternative treatment options when prescriptions aren’t evidence-based.
When prescriptions are cancelled, renewed or modified, electronic medical record systems could prompt physicians to record details about adverse drug reactions and effectiveness, which would also ensure that details about a patient’s treatment history and experiences with past therapies are documented.
Many Canadian provinces have implemented centralized drug-information systems to track all medications that patients are receiving. If these systems are to contribute toward an effective, post-market, drug-surveillance system, they need to additionally collect information on the reasons why medications are being prescribed and the outcomes that they produce.
Medications can be life-saving. But they’re only as good as our knowledge about them. It’s time we stepped up our game and kept better track of our experiences with medications.
Jenna Wong will begin a post-doctoral research fellowship in the department of population medicine at Harvard Medical School beginning in 2018. Robyn Tamblyn is an expert adviser with EvidenceNetwork.ca and James McGill is a professor in the departments of medicine and epidemiology, biostatistics and occupational health at McGill University in Montreal.
Beware, Drug Manufacturers – You May Actually Have to Face the People You Hurt
The Supreme Court of the United States may be best known for hearing cases that capture the attention and imagination of the American public, but that is not all they do. In fact, on October 2, 2017, the Supreme Court of the United States heard motions on a case that we have been paying close attention to, even if the public at large has not. That case involved GlaxoSmithKline, LLC, the manufacturers of the popular anti-depressant Paxil.
GSK is a UK company, but its American division is headquartered in Philadelphia and incorporated in Delaware. Paxil is sold in pharmacies throughout the country. In a 2014 lawsuit filed in Illinois, 16 people – 8 mothers and 8 children, from 6 different states (including Illinois) – claimed that Paxil, when ingested by the mothers during their pregnancy, led to congenital, catastrophic birth defects in the children. The lawsuit against GSK alleged:
“strict liability and failure to warn,
strict products liability and design defect,
breach of implied warranty,
breach of express warranty, and
negligent misrepresentation and concealment.”
GSK, of course, moved to dismiss the case, claiming “it was not subject to general jurisdiction because Illinois is neither the state of its incorporation nor its principal place of business.” Furthermore, they claimed:
“Illinois lacks specific jurisdiction because the out-of-state plaintiffs’ claims did not arise from its Illinois activities. Moreover, defendant GSK claimed that its actions or omissions in Illinois were not the ‘but for’ cause of the alleged harm: plaintiffs did not serve as study subjects in Illinois, did not receive Paxil prescriptions in Illinois, did not ingest Paxil in Illinois, and did not suffer injury from Paxil in Illinois. Finally, defendant GSK argued that the out-of-state plaintiffs may not create personal jurisdiction by tacking their claims onto those of the two Illinois plaintiffs.”
A lower court ruled against GSK, which then attempted to appeal to the Illinois Supreme Court. When that, too, failed, they went to the Supreme Court of the United States – and the Supreme Court denied their petition for a writ of certiorari, which means the lower court’s decision stands.
Why this denial is important for victims of dangerous drugs
“Personal jurisdiction” has been used as an argument by drug companies before, to avoid lawsuit filings in states that are deemed “less friendly” to those companies – or, in layman’s terms, in states where a strong civil justice system exists to protect people, not profits. The decision of the Supreme Court, to allow the original decision to stand, sets a precedent for other drug companies seeking to use the same loopholes to avoid lawsuits over dangerous and defective drugs.
It also holds these drug companies accountable for their actions in the states where those actions are committed. GSK held between 18 and 22 clinical trials in Illinois. Even though the plaintiffs in this case were not a part of those trials, one cannot deny that GSK has significant ties to that state. This renders their argument that Illinois has no jurisdiction moot. And as trials like these can (and do) happen in all 50 states, drug companies can be tied to actions in all 50 states, meaning plaintiffs can file lawsuits with confidence in regard to jurisdiction.
There will always be exceptions, of course. Not every case will proceed as this one did, nor will every case move on to be heard by the Supreme Court. But for those of us who fight on behalf of victims, this is a “win”: for our clients, and for the civil justice system.
Plattner Verderame, P.C. offers honest guidance and aggressive representation for injured clients throughout Arizona. If you were harmed because of a defective medical device or dangerous drug, our Phoenix product liability lawyers are here to help. Please call us at 602-783-8793, or fill out our convenient contact form, to learn more.
US Supreme Court Refuses to Restrict Personal Jurisdiction in Landmark Paxil Case
Posted by Kenneth Brennan
October 2, 2017 1:35 PM
Today, the U.S. Supreme Court allowed to stand an appellate court decision stating that a product manufacturer is subject to personal jurisdiction for product-related claims in a state where development or testing occurred, dealing a huge blow to the well-funded big pharma legal teams who may well now find themselves defending their drugs and medical devices in all fifty states.
The U.S. Supreme Court denied cert on M.M. ex rel. Meyers v. GlaxoSmithKline LLC, letting stand an Illinois appellate court case that held that GlaxoSmithKline, a UK company with U.S. headquarters in Philadelphia, would need to defend itself in Illinois state court for catastrophic birth defect injuries resulting from pregnant mothers’ use of its anti-depressant, Paxil. The Meyers case alleges the drug injured eight minor plaintiffs from six states, including Illinois. The Illinois Supreme Court had already refused to hear GSK’s appeal from the appellate decision. Unsatisfied, GSK appealed to the U.S. Supreme Court, which refused to upset the decision of the Illinois appellate court.
The Illinois appellate court previously found that Illinois had personal jurisdiction over GSK based on the defendant’s substantial in-state contacts, namely its contracts with 17 Illinois physicians to participate in 18 to 21 clinical trials on Paxil in Illinois as part of multicenter studies, and the fact that the plaintiffs’ claims arose from the defendant’s acts or omissions related to those trials.
Clinical studies involve research using participants (humans) to evaluate the health outcomes of a particular drug, device, procedure, or behavior. Generally, these clinical studies are performed by investigators funded by drug companies that are required to submit studies to the Food and Drug Administration. The principal investigators are generally medical doctors who may be part of a hospital, university, clinic, or general practitioner’s office. These studies generally happen in all 50 states, and the data are usually consolidated and submitted to the FDA. Drug companies often also publish results in medical journals.
Today, the U.S. Supreme Court chose to let that case stand by denying the defendant’s petition for a writ of certiorari, which is a written request for the U.S. Supreme Court to review a lower court’s ruling. The denial of a petition for a writ of certiorari by the U.S. Supreme Court means the decision of the lower court stands as the final decision.
The plaintiffs in Meyers are represented by TorHoerman Law. Robert Peck of the Center for Constitutional Litigation also represented the Plaintiffs before the U.S. Supreme Court. TorHoerman Law partner Ken Brennan wrote the successful Illinois appellate brief. Brennan says,
“While industry does not like the result, the result makes perfect sense with respect to clinical trials from which the plaintiffs’ claims arise. Drug manufacturers treat multi-center clinical trial data as a unitary whole and aggregate the data collected in various states to reach statistically significant conclusions. The portions of the clinical trials that occur in a particular state, however small, cannot be separated from the rest. And, because inadequate clinical trials naturally lead to inadequate warnings, failure to warn claims arise from or relate to those trials.”
The fact that the claims made in the case arise from or relate to those trials provides a basis for the lawsuit to be heard in the state where the trials occur.
The Meyers decision undermines previous industry efforts to limit personal jurisdiction to drug manufacturers’ preferred jurisdictions under the Daimler AG v. Baumann and BMS v. Superior Court of California cases, both decided by the U.S. Supreme Court. Since the U.S. Supreme Court chose not to hear the Meyers case, it left open the opportunity for plaintiffs alleging injuries that arise out of or relate to clinical trial data to sue manufacturers in the states where the trials occurred. Meyers restores some degree of fairness to consumers injured by drug manufacturers.
TorHoerman Law founder Tor Hoerman released the following statement in response to the Supreme Court’s refusal to hear the Meyers appeal:
“Four years ago, lawyers for GSK told me that they would not pay these children and their families. We told GSK that we would file these cases in Cook County. The lawyers told us we were crazy, that they would tie us up in the appellate courts and we would be in litigation for years. I promised GSK that day that we would pursue these cases for these deserving families until a court told we could no longer do so. Well, GSK has kept its promise, and we will keep ours. The highest court in the land told them they have to litigate in Cook County. What will they do now? The right thing? We shall see. GSK and our clients can rest assured that Ken Brennan and the lawyers at THL will not quit on these cases.”
Daimler AG v. Bauman, 134 S. Ct. 746 (2014) (which curtailed general jurisdiction) and Bristol-Myers Squibb Co. v. Superior Court of California, San Francisco Cty., 137 S. Ct. 1773, 198 L. Ed. 2d 395 (2017)
M.M. ex rel. Meyers v. GlaxoSmithKline LLC, 2016 IL App (1st) 151909, 61 N.E.3d 1026, appeal denied sub nom. M.M. v. GlaxoSmithKline LLC, 65 N.E.3d 842 (Ill. 2016)
VANCOUVER—A proposed settlement has been reached in a lawsuit filed by a woman who alleges her daughter suffered a birth defect after she was prescribed the anti-depressant Paxil during pregnancy.
Rosenberg Law, a Vancouver firm that filed the class-action lawsuit involving about 50 mothers and their children, says it has reached a $6.2-million settlement with GlaxoSmithKline Inc.
In a statement on Wednesday, the pharmaceutical company says it has agreed in principle to settle the lawsuit but it does not admit to any liability or wrongdoing as part of the agreement, which must still be approved by the Supreme Court of British Columbia.
Faith Gibson of British Columbia was named as the representative plaintiff in the suit after her daughter Meah Bartram was born with a hole in her heart in 2005.
Gibson’s initial statement of claim filed in B.C. Supreme Court in 2012 alleged that Paxil increased the risks of damage to the heart and lungs of newborns, who it contends were unable to breath properly due to constricted blood vessels.
GlaxoSmithKline says patient safety is its “highest concern” and it continues to believe that it provided accurate and updated information on Paxil to regulators, and also communicated safety information to regulatory agencies, the scientific community and health-care professionals.
The company says it agreed to the proposed settlement “to avoid the time and expense associated with the trial and the subsequent steps in the class-action proceeding.”
“We continue to be of the view that the scientific evidence does not establish that exposure to Paxil during pregnancy causes cardiovascular birth defects.”
Rosenberg Law says as many as 200 children in Canada could benefit from the settlement.
In a decision released in 2013 upholding the class-action lawsuit, the B.C. Court of Appeal said the company sent a letter to health professionals in September 2005 that referred to preliminary results about a study that showed an increased incidence of cardiovascular defects in babies born to women who took Paxil during the first trimester of pregnancy.
Gibson’s daughter was born about two weeks before the company sent the letter to doctors.
In February 2006, the company amended the product label to outline the potential problems that might arise.
The plaintiffs alleged in court that the company knew or ought to have known of the risk before then.
In their Zofran lawsuits, hundreds of families accuse GlaxoSmithKline of guiding a sweeping – and illegal – marketing campaign to convince obstetricians into prescribing the nausea drug as an off-label treatment for morning sickness. The company’s attorneys are now petitioning the US District Court of Massachusetts to have those claims of marketing fraud thrown out.
GSK Moves To Throw Out Zofran Marketing Claims
In some sense, the defense attorneys are simply asking Judge F. Dennis Saylor to follow through on one of his previous decisions. On April 24, 2016, Judge Saylor ruled that plaintiffs’ allegations of an illicit marketing campaign were “too broad” to be heard in court. Now, GlaxoSmithKline is urging the Court to strike those allegations from the record, claims that the company’s lawyers have dubbed “immaterial.” This isn’t an idle request, though.
After quashing the allegations of fraudulent marketing, Zofran’s manufacturer would like Judge Saylor to limit the scope of discovery, effectively blocking the families from accessing corporate documents on the sales visits that company representatives conducted with individual doctors. Many families have said that GlaxoSmithKline’s sales representatives routinely misrepresented the safety and efficacy of Zofran during their consultations – at the behest of corporate executives. While the company vigorously denies this accusation, it now hopes to block plaintiffs from the very evidence that would either confirm or disconfirm their beliefs.
Fight Continues Over Federal Investigation Communications
This isn’t the only front on which GlaxoSmithKline is fighting plaintiffs’ ability to access potential evidence of wrongdoing. In the late-2000s, the company came under federal investigation. Investigators from the US Department of Justice had been tipped off by a whistleblower lawsuit filed in 2003, which accused GlaxoSmithKline of orchestrating numerous illegal marketing campaigns. As two former high-level corporate employees related, their employer had regularly advertised FDA-approved products for off-label indications, flouting federal law in the process. Zofran had been specifically marketed as a morning sickness treatment, the men said.
The federal government soon took the case on. After years of intense scrutiny, the federal investigation yielded a stunning result. In 2012, GlaxoSmithKline agreed to plead guilty to three criminal charges, the Justice Department reports, notably “two counts of introducing misbranded drugs, Paxil and Wellbutrin, into interstate commerce.” Moreover, the company agreed to pay $2 billion to resolve the government’s civil allegations, including accusations that Zofran had been marketed illegally.
While some details from this investigation have been made public, most of the specifics remain locked in GlaxoSmithKline’s corporate servers. Families are clamoring to obtain these documents, hoping to understand the finer points of the company’s Zofran marketing strategy. In fact, the US District Court of Massachusetts has already ruled that plaintiffs’ have a right to this information, despite GlaxoSmithKline’s arguments to the contrary.
On April 6, 2017, Magistrate Judge Judith G. Dein denied the corporation’s request for a protective order that would have paused discovery into the documents. GlaxoSmithKline believes that, if the allegations of fraudulent marketing are thrown out, any discovery into the company’s communications with federal investigators should be ruled out as well. After all, and by the company’s own admission, “the DOJ investigation focused on whether the defendant’s sales force had provided false information to physicians.”
Judge Dein, though, felt that the discovery in question could well impinge on allegations beyond those of fraudulent marketing. For example, the families claim that GlaxoSmithKline was “negligent” in warning the medical community of Zofran’s alleged risks. This isn’t a fraud-related allegation, but halting discovery into the company’s communications could have the unintended consequence of preventing plaintiffs’ from gaining evidence to support their negligence-based claims. To avoid that pitfall, Judge Dein felt it was appropriate to compel GlaxoSmithKline to produce documents related to the Justice Department investigation.
The company has yet to produce these documents. Despite Judge Dein’s court order, issued on April 6, 2017, plaintiffs’ attorneys say GlaxoSmithKline is only “constructing new methods of delay and obstruction.” In a new motion to compel the documents filed on May 8, the families have asked the Court to force their opponent into making the information available.
As of May 9, 2017, a total of 366 Zofran birth defect lawsuits have been consolidated in the US District Court of Massachusetts. Judge F. Dennis Saylor has been guiding the litigation through coordinated pre-trial proceedings. Relying on a series of large epidemiological studies, parents from across the country say the potent anti-nausea drug can cause major birth defects, including cleft palate and various forms of congenital heart disease.
L-R: Jon, Nicholas and Clara Rickman. (Source: WBRC video)
At only five days old, baby Nicholas underwent his first of three heart surgeries. Source: Jon and Clara Rickman
Clara Rickman and her son Nicholas. Source: WBRC video
BIRMINGHAM, AL (WBRC) – Over 200 lawsuits allege that pregnant mothers prescribed Zofran, or a generic equivalent, caused them to have babies born with congenital birth defects.
Jon and Clara Rickman, of the Birmingham area, are plaintiffs in one such lawsuit. They say their baby, Nicholas, was born with congenital heart defects after his mother took the generic form of Zofran, called “ondansetron,” to alleviate her morning sickness during her first trimester.
At only five days old, Nicholas underwent his first of three heart surgeries.
Nicholas’ mother blames herself for taking the drug.
“Every day, you see his scar. And I can’t never fix it and I think it’s my fault,” said Clara.
The Rickmans say if Clara had not taken the generic form of Zofran, Nicholas would not have been born with a heart problem. According to their lawsuit, there is no family history of his conditions and there are no signs of a genetic cause.
The Rickmans are speaking publicly about their lawsuit and Nicholas’ health because they believe they can prevent a similar fate for others.
“I don’t want other mothers to go through what I’ve been through. And I don’t want them to feel guilty for the rest of their life, like I do,” Clara said.
Zofran was FDA-approved in 1991 to prevent post-operative nausea, and to help cancer patients alleviate nausea during chemotherapy treatments. It was not FDA-approved for treatment of morning sickness.
“It’s never been tested in pregnant women for safety and for safety in unborn children,” said the Rickman’s lawyer, Don McKenna, a partner at Hare Wynn in Birmingham.
McKenna says physicians began prescribing Zofran for uses other than what is FDA-approved. This is called an “off-label” prescription, and according to Peter J. Hughes, Pharm. D., such prescriptions are not uncommon.
“The estimates are that as many as one in five prescriptions written and filled in a pharmacy is for an off-label use, so that’s 20 percent,” said Dr. Hughes.
A professor at Samford University’s McWhorter School of Pharmacy, Dr. Hughes is an expert in drug information and off-label use.
“It’s nothing to lose sleep over, but I do think it’s important for patients to know what they’re taking and why they are taking it,” he said. “The medication in their medicine cabinets may be used for a purpose that’s not associated with original intended use of the drug product.”
Dr. Hughes says patients should initiate a conversation with their doctors about prescriptions. He says patients should ask: Why I am receiving this prescription? Is this an off-label prescription? If so, what is the level of evidence supporting the decision to prescribe it to me?
Clara says she was never advised by her OBGYN that Zofran was not tested on pregnant women. Her lawyer believes that is a problem.
“It’s being continued to be prescribed today off-label because a doctor can prescribe off-label for any use they believe is necessary,” said McKenna. “What we don’t believe they’ve been told by the pharmaceutical company is that this has never been tested for use in pregnant women and safety in their children.”
The Rickmans are suing GlaxoSmithKline, manufacturers of Zofran, alleging that the drug company illegally marketed the drug for use in pregnant mothers and withheld information about the drug’s safety and effectiveness.
McKenna explained it is illegal for a drug company to market an FDA-approved drug for an off-label use.
“You can only market a drug that has been approved for use by the FDA and they never sought approval for use in pregnant women,” he said.
The Department of Justice (DOJ) previously accused GlaxoSmithKline of illegally promoting the off-label use of Zofran for the treatment of morning sickness in pregnant women. The DOJ alleged that GlaxoSmithKline paid kickbacks to doctors to induce them to prescribe Zofran and other drugs. The company settled those claims, without admitting liability, in 2012.
In a statement, a spokesperson for GlaxoSmithKline said, “There have never been any findings that GSK illegally marketed Zofran at any time. In 2012, GSK agreed to include Zofran in a larger settlement with the government in order to avoid the distraction and expense of litigation.”
GlaxoSmithKline paid over $3 billion for the total settlement, which included criminal and civil charges. It remains a settlement that the DOJ calls the largest combined federal and state health care fraud recovery in a single global resolution in the history of the United States.
Though the FDA does not regulate the off-label use of prescription drugs, it collects data about adverse events associated with use. The FDA has more than 5,000 adverse events involving Zofran reported by a patient, health care provider, or manufacturer. While reporting of adverse events is optional for consumers and healthcare providers, reports are mandatory for drug manufacturers.
More than 400 adverse events from Zofran are reported for “maternal exposure during pregnancy.” More than 300 adverse events are associated with “foetal exposure during pregnancy.” There are 170 adverse events reported for “congenital anomaly.”
These reports were reviewed and considered by the FDA when it issued a public letter in October 2015 about Zofran. The letter responded to a Citizen’s Petition filed with the FDA in January 2013 requesting that the agency reclassify the drug with stronger warnings of potential risks associated with its use by pregnant women.
The Citizen’s Petition also wanted OBGYNs to be notified that Zofran may lead to adverse maternal and fetal outcomes.
After reviewing the medical literature studying the off-label use of Zofran, the FDA denied the Citizen’s Petition.
A GSK spokesperson pointed to this FDA letter and said, “They found that the evidence did not support a conclusion that there is an increased risk of adverse fetal outcomes or birth defects from exposure to Zofran during pregnancy.”
Dr. Hughes has also reviewed the FDA letter. He explained that the denial is based on a review of publicly available published medical studies. It did not include a medical study initiated by the FDA.
According to Dr. Hughes, the letter concludes that current available medical literature is inadequate to support a definitive conclusion on whether there is an increased risk of fetal outcomes when pregnant mothers take Zofran.
“The studies that are published cannot support conclusions on whether there is an increased risk,” he said.
The FDA was critical of these studies because, “they were not the highest quality, had low sample sizes, and/or were retrospective studies.”
The FDA letter, itself, recognized, “While a potential association between use during pregnancy and cardiovascular malformation warrants continued vigilance, given the limitations…the study does not support a change in the pregnancy risk category at this time for those products.”
And with regard to its denial of the request to notify physicians about alleged adverse outcomes, the letter stated, :FDA does not believe that such an unusual notification is warranted in this case.”
“Absent a compelling legal or public health concern, FDA generally does not comment on the number or quality of studies regarding the efficacy of a drug product for an unapproved use or provide notification to health care providers regarding its relative efficacy as compared to other drug products for such unapproved use,” the letter stated.
The federal judge presiding over the Zofran litigation, including the Rickmans’ lawsuit, also reviewed the FDA’s response letter. He noted that GSK could be in possession of additional information that the FDA did not consider.
“If – as plaintiffs allege – GSK was in exclusive possession of information not previously submitted to the FDA indicating a need for a new or strengthened warning…that information could not, however, have been submitted by a citizen petition, as no citizen (according to plaintiffs) had access to it,” wrote U.S. District Judge F. Dennis Saylor, IV.
The Rickmans’ lawyer says the next 12 months, or more, will be spent collecting and reviewing internal company documents from GSK about the development, testing, and marketing of Zofran. It could be three to five years before these cases are ready for a trial.
In the meantime, the Rickmans will raise Nicholas. About one year after his heart surgeries, Clara says baby Nicholas is doing better.
“I want him to know that he’s a really strong baby, that he’s a fighter, and that he should be proud of about it,” said Clara.
“If I could go back,” she said with tears streaming down her face, “I would never take anything, if I knew it would hurt him.”
Most Drugs Aren’t Tested on Pregnant Women. This Anti-nausea Cure Shows Why That’s a Problem
For years, Zofran was the most popular morning-sickness medication in the U.S. Now it’s being accused of causing birth defects. The larger issue is a drug-safety system that excludes women from clinical trials, potentially putting them and their babies at risk.
Marquita Smiley’s first surprise was discovering she was pregnant. Her second was how miserable being pregnant felt. With her older daughter, she had experienced some mild queasiness. This time, the nausea and vomiting were so bad, “I would be calling off work and not wanting to get out of bed.” As a single mom in Birmingham, Alabama, and a social worker who investigated horrific cases of child abuse, she didn’t have that option. Her ob/gyn wrote a prescription for Zofran, generic name ondansetron, which had been developed for cancer patients ravaged by radiation and chemotherapy but had become the preferred treatment for extreme morning sickness. The pills melted in Smiley’s mouth, dissolving the nausea with them. “I felt so much better,” she said. “So we just kept kinda going with it.”
Fifty to 90 percent of women spend some part of their early pregnancies sick to their stomachs, and what begins as simple nausea can become dangerously debilitating. Some expectant women use ondansetron for only a few days; Smiley took it two or three times a week into her second trimester. In her fifth month, an ultrasound showed that the left side of her baby’s heart was critically underdeveloped. Three days after her son, Zaidan, was born in April 2014, cardiologists at the University of Alabama Hospital in Birmingham performed open-heart surgery, but a blood clot caused the baby to have a heart attack and his kidneys began to fail. Somehow Zaidan hung on: At two months, he had a heart transplant; at four months, he went home.
Smiley was torn between feeling extraordinarily lucky — Zaidan was her “miracle baby” — and blaming herself for his suffering. As his first birthday neared, one of her coworkers mentioned she’d seen TV commercials by a law firm claiming that Zofran might cause serious congenital heart problems and other birth defects.
Smiley began doing her own research. She had assumed that medications prescribed in pregnancy are tested and monitored for prenatal use, perhaps even more carefully than other drugs. But ondansetron, for years the most widely used drug to treat the most common complication of pregnancy, was never approved in the U.S. or anywhere for use in pregnancy. The pharmaceutical giant GlaxoSmithKline vigorously denies Zofran causes birth defects, and most research so far seems to support that claim. Smiley acknowledges she can’t be certain what caused Zaidan’s problems. But if she’d known the drug hadn’t been approved for prenatal use, she said one morning in her lawyer’s office, distracting her squirmy toddler with Goldfish crackers, “I would not have placed him at risk.”
A healthy baby is the universal goal of pregnancy, shared by women and doctors, researchers and regulators alike. The nine months from conception to birth are extraordinarily dynamic and complex, and the complications that arise can have lifelong effects. There’s a critical need for knowledge about almost everything, from environmental causes of birth defects to how the mother’s preexisting medical conditions can affect her baby’s well-being.
Yet the same desire to protect the fetus often deters scientists and drug makers from studying the expectant mother. When it comes to drug safety, pregnancy is a largely research-free zone, women’s health experts say. The consequence? Treatment that often is based on informed guesswork rather than solid evidence, in which medications that have never been approved for use during pregnancy, and whose long-term dangers may not be known, become the standard of care. Zofran is a case study in just how problematic this system has become.
Zofran is far from unique — almost every drug prescribed during pregnancy in the U.S. is “off label,” meaning it hasn’t gone through the clinical trials required by the Food and Drug Administration before approving a drug for a specific use in a specific population. Only eight medications are currently approved by the FDA for prenatal use; from 1995 to 2011, the agency OK’d only one pregnancy-related drug. (By contrast, 29 drugs to treat cardiovascular-related conditions have won approval just since 2010.) Pregnant women have become what researchers and ethicists call“therapeutic orphans,” reliant on drugs of uncertain risk, sometimes during the earliest and most vulnerable stages of fetal development.
The problem goes back to efforts to protect women and babies from the kind of severe birth defects and other harm caused by thalidomide and other drugs in the 1960s and ‘70s — and pharmaceutical companies from legal liability for those injuries. Decades later, “pregnant women may be the most underrepresented group in the entire clinical research process,” a 2011 report by the National Institutes of Health’s Office of Research on Women’s Health declared. In a 2013 analysis, 95 percent of industry-sponsored clinical drug trials excluded expectant mothers; a mere 1 percent were designed specifically to study them.
Yet according to the Centers for Disease Control, as many as 9 in 10 expectant mothers use medications — for ailments that occur before they even realize they’re pregnant; for complications such as morning sickness, early labor, or gestational diabetes; for chronic conditions such as epilepsy, high blood pressure, or depression that often become more challenging to manage as the months pass. Hampered by a lack of peer-reviewed evidence and hard data, ob/gyns find themselves in the dark about some basic best practices: How does a drug work in an expectant woman’s body? What’s the right dose to take and the right time to take it? What are the true risks to the fetus (or lack thereof)?“Pregnant women are not like non-pregnant people,” observed Susan Wood, director of the FDA’s Office of Women’s Health from 2000 to 2005 and now an associate professor of health policy at George Washington University. “They have a different fluid volume ratio, a different metabolism … all sorts of [physiological] changes that could affect how well a drug works.”
Fewer than 10 percent of medications have enough information to determine their safety for prenatal use, the CDC notes. Off-label use of a drug during pregnancy thus becomes a kind of unregulated, unmonitored clinical trial. “We learn on the backs of [pregnant] women while pretending we don’t experiment on pregnant women,” said Ruth Faden, director of the Johns Hopkins Berman Institute of Bioethics. “But in fact, we do.” By the time the real risks become apparent, several decades may pass. The watchdog group Public Citizen analyzed how long it can take the FDA to issue a “black box” warning after problems surface with a drug. The average: 27 years after the drug was approved.
In the absence of reliable information, sometimes mothers-to-be and their physicians conclude the risks are too great and stop a medication that’s really needed, triggering an avoidable medical emergency that can do more harm than the drug itself. “If research is important to tell us when medications are unsafe, it is also important to reassure us when drugs are safe,” Faden and a group of women’s health advocates calling themselves the Second Wave Initiative argued in a recent manifesto.
The question of how to improve research on pregnant women has greater urgency as new threats such as the opioid epidemic and the Zika virus have emerged. As policy makers, medical organizations and women’s health experts grapple for a solution, the most intractable problem may be a deep-rooted cultural bias that elevates the fetus above all else. “There’s been a dogma in which pregnant women come last,” Faden said. “Always last.”
Meanwhile, Marquita Smiley and other women are often left with no clear options or answers — and little or no recourse if something goes very wrong. It’s an awful position to be in, Smiley said. “I’m trying to find the words.”
Not so long ago, doctors viewed nausea and vomiting of pregnancy (the medical term for morning sickness, abbreviated as NVP) as largely a psychological problem, at its worst a sign that a woman was so unhappy being pregnant she literally wanted to throw up her fetus. Now, the key culprit is believed to be the hormone human chorionic gonadotropin, which is produced in the placenta and surges through a woman’s body as the embryo begins its rapid growth. Studies suggest that some nausea is actually a healthy sign, with mothers who suffer from it less likely to miscarry or go into premature labor. But up to 2 percent of pregnant women develop hyperemesis gravidarum (HG), nausea and vomiting so serious it can require hospitalization — Charlotte Bronte is believed to have died from it. As with so much else about pregnancy, the long-term effects of hyperemesis are mostly unknown: “Because they see HG as a maternal disorder that lasts three months, they don’t fund the research for it,” said Kimber MacGibbon, founder of the HER Foundation, a patient advocacy group.
Three decades before Zofran arrived on the scene, thalidomide seemed like an answer. The German drug was marketed as a sedative and sleeping pill. But it also eased nausea and was believed to pose no dangers to human fetuses — until women began giving birth to babies with severely deformed limbs. After thalidomide was banned in the early 1960s, doctors and women relied on a drug called Bendectin that had received FDA approval in the 1950s specifically for morning sickness and had a long track record for safety; still, lawsuits eventually blamed it for fetal harm, ranging from skeletal malformations to blood disorders and cancer. The claims proved to be unfounded, but in 1983, the litigation-weary manufacturer voluntarily yanked it from the market. For the next 30 years, there was no FDA-approved treatment for NVP.
Other reproductive-health scandals erupted over the cancer-causing synthetic estrogen DES, which was prescribed to prevent miscarriages, and the potentially deadly Dalkon Shield intrauterine device, used to prevent pregnancy. In their aftermath, the ethical and scientific pendulum swung in the direction of extreme caution.
Pharmaceutical companies and regulators concluded that the best way to avoid injuring women and their offspring — and the resulting crush of lawsuits — was to stop doing research on all women. “The fear of bad outcomes in pregnancy led to this sort of general exclusion,” said Wood, the former FDA official. In 1977, the FDA issued formal guidelines stating that women of “childbearing potential” — i.e., anyone who had not gone through menopause or been surgically sterilized — could only be included in late-stage clinical trials, after the safety and effectiveness of a drug had already been established (a rule widely interpreted as “never”).
Thanks in large part to the furious lobbying of feminists and anti-AIDS activists, the FDA finally reversed its stance against most women in research in 1993. But pregnancy remained a conundrum. The influential Institute of Medicine argued in a report co-edited by Faden, that “If a drug is going to be used in pregnant women, then the availability of safety and effectiveness information” is critical, including “adequate information about the risks and benefits.” Moreover, pregnant women should be “treated as competent adults capable of making their own decisions.”
Yet, widespread aversion to prenatal research persisted. The National Institutes of Health continued to categorize pregnant women as “vulnerable,” with a “questionable” capacity to give informed consent — in the same category as kids, prisoners, and the mentally disabled. Conducting research on mothers-to-be was complicated and costly, and women themselves were often hesitant to sign on. “We honestly haven’t really addressed the issue of actively trying to recruit pregnant women into clinical trials,” a research expert for the drug industry said in a recent interview, speaking on the condition of anonymity. A 52-page document by the Pharmaceutical Research and Manufacturers of America, outlining principles for conducting clinical trials and revised in 2015, doesn’t contain a single reference to pregnancy.
Physicians responded by doing what they have always done: They prescribed drugs to pregnant patients “off label,” and shared the benefits and potential risks in medical journals and at conferences. The scientific establishment and the FDA consider this part of the basic practice of medicine, beyond the scope of regulators. The result was something of a vicious cycle, Faden said. “If your product eventually will be used in this population anyway, off label, what’s your incentive for testing the drug in pregnant women before it’s approved?”
Zofran’s introduction in 1991 occurred in the midst of this research vacuum. The drug worked by blocking the action of the chemical serotonin in the brain’s so-called vomiting center. It had been extensively tested on cancer and surgical patients, and on pregnant rats and rabbits. These studies showed “no evidence of impaired fertility or harm to the fetus,” the FDA-approved package insert said. But because animal studies are imperfect predictors of human toxicity and there were “no adequate and well-controlled studies in pregnant women,” the drug “should be used during pregnancy only if clearly needed,” the label added.
Plenty of ob/gyns believed it was needed — desperately. The journal Lancet soon published letters from doctors in Greece and Britain who had used Zofran on patients with severe hyperemesis. Physicians in Hong Kongdescribed a patient so weak that she had considered having an abortion — until the drug turned her pregnancy around. The HER Foundation’s MacGibbon had HG with both her kids, and the drug was such a salvation that she and her husband joked about naming their daughter “Zofrana.” As a registered nurse, she understood the off-label dilemma, “but I knew that if I didn’t [take it], literally, I would just sit there and puke until I couldn’t breath.”
By the time Marquita Smiley was pregnant with Zaidan in 2013, Zofran/ondansetron was available in both liquid and pill form and as a generic from 30 or so manufacturers. The online price for 30 pills had plummeted from nearly $800 to $26. Last year, more than 21 million prescriptions were filled in the U.S. for all uses of the drug, according to an analysis by IMS Health — 10 times as many as in 2006. Doctors were no longer reserving the drug for only the most difficult cases, said Smiley’s lawyer, Don McKenna of the Birmingham law firm Hare Wynn. “It got to the point where if anyone complained of an upset stomach, they would get a prescription.”
Although doctors may decide to prescribe a medication for unapproved uses, it’s illegal for drug companies to encourage them to do it. In 2012, the U.S. Justice Department announced that GlaxoSmithKline had crossed the line.
The allegations originated with ex-Glaxo marketing execs turned whistleblowers. The DOJ accused the company of engaging in all kinds of banned behavior to drive up sales — plying doctors with Caribbean vacations and hunting trips, misreporting clinical trial findings to a medical journal, withholding safety data from the FDA. The most serious, criminal charges covered the antidepressants Paxil and Wellbutrin and the diabetes drug Avandia. But in a civil settlement, DOJ said Glaxo had also spread “unsubstantiated and/or false representations” about Zofran’s use for morning sickness and “paid illegal remuneration” to doctors to promote and prescribe the drug, in violation of federal anti-kickback laws. Glaxo didn’t admit any wrongdoing where Zofran was concerned, but it pleaded guilty to fraud in connection with other drugs and paid a $3 billion fine, the largest ever levied against a drug maker. (Read ProPublica’s reporting about another drug in the civil case, the asthma medication Advair, here.)
The DOJ case hit the news at a delicate moment. For years, reports in medical journals raised few concerns about the Zofran’s use in pregnancy, but they were small and frequently observational — hardly the scientific gold standard. By 2012, however, large-enough numbers of pregnant mothers had used the drug to conduct more meaningful analyses. Researchers associated with the National Birth Defects Prevention Study found an increased risk of cleft palate in infants whose mothers had used ondansetron (a separate, unpublished analysis detected a “modest increased risk” of the type of heart problem suffered by Marquita Smiley’s son). Next came studies based on medical registries in Denmark and Sweden that tracked every pregnancy in those countries going back to the 1990s. One found no difference in birth defects between the Zofran-exposed and unexposed babies; another found an elevated risk — up to twice as high — of hole-in-the-heart defects.
Among scientists, the inconsistent studies triggered calls for more research but no major alarms. Birth defects afflict 3 percent of babies, and heart defects are the most common among them. If ondansetron does harm the fetus, “It absolutely can’t be anything huge or we would have already seen it,” said Christina Chambers, a professor at the University of California, San Diego School of Medicine who is a leading expert on environmental exposures and pregnancy.
Plaintiffs lawyers, though, thought they saw plenty of red flags. Over the next couple of years, they hired their own experts and began digging through everything from adverse-event reports filed with the FDA (more than 450 involving prenatal exposures), to the LinkedIn profiles of Zofran sales people, to obscure Japanese medical journals in which scientists working for Glaxo had published animal studies in the early 1990s.
By this spring, parents had filed more than 200 lawsuits, alleging that Zofran caused heart defects, cleft palates, and kidney problems in babies exposed to the drug in utero; in a few instances, the babies died. Lawyers contended there might be many more cases but for recent U.S. Supreme Court rulings that make it almost impossible for consumers in all but a few states to sue for injuries if the medication at issue was a generic version of a brand-name pill, as ondansetron is for Zofran. One state whose courts did allow such lawsuits was Alabama — until legislators there rewrote the law in 2015. Marquita Smiley, who took generic ondansetron, filed her lawsuit last fall, just before the courtroom doors slammed shut.
In a written statement, Glaxo said the allegations linking Zofran to birth defects are “entirely unfounded,” and pointed to the FDA’s rejection last fall of a citizen’s petition that had sought stronger pregnancy warnings on the label. The company said doctors have a right to “assess the health care needs of their patients and apply their own knowledge, training, and experience in deciding whether the therapeutic benefits of a medicine outweigh the potential risks in each patient.”
But plaintiffs’ lawyers argue that drug makers have a heightened responsibility to assure that medications likely to be used in pregnancy are safe — especially if they are used to treat a condition as common as morning sickness, and if they are marketed off-label.
“When you throw a stone in the water, you have to expect there will be ripples,” said Tobias Millrood, a Philadelphia lawyer who is one of the lead counsels. “It’s really quite that simple.”
Under Alabama law, a woman who uses illicit drugs while pregnant can be arrested, prosecuted and stripped of her parental rights — even if she was just using marijuana to treat her morning sickness. Smiley’s agency, the state Department of Human Resources, is the one often called upon to investigate allegations that pregnant women and new mothers have chemically endangered their babies. Smiley doesn’t handle those kinds of cases, but she knows irony when she sees it: A woman could face 10 years in prison for endangering her unborn child with drugs, while a huge corporation could put children at risk with a drug that’s never been approved for use in pregnancy.“It’s crazy,” she said.
Take a Valium, Lose Your Kid, Go to Jail
In Alabama, anti-drug fervor and abortion politics have turned a meth-lab law into the country’s harshest weapon against pregnant women. Read the story.
In her lawyers’ office one late winter morning, Zaidan was sweet-tempered and surprisingly sturdy, exploring the unfamiliar environment with sippy cup in hand. But his skin was blotchy and his hair had been falling out. The transplant drugs have wreaked havoc on his immune system, and he spent most of March in the hospital with breathing and other problems. As much as Smiley worries about his physical health, she’s just as concerned about his cognitive and emotional development. “He had a lot of loss of oxygen to his brain early on,” she said. She has to protect him from infections, which means keeping him way from a lot of people, “and I know that’s bad because he needs social skills.” Thanks to her job, she knows where to get help: “The social worker in me had him sign up for early intervention….I’m on the receiving end of the services now.”
With so much to worry about, she hasn’t been paying much attention to the lawsuit. Glaxo lost a bid earlier this year to have the cases dismissed, and now the litigation is in its discovery phase: “GSK has to put all its cards on the table and say … ‘This is everything we knew,’” attorney Don McKenna said. The latest research has not gone in the plaintiffs’ favor: A new study looking at birth outcomes in more than 1,000 women who took Zofran or ondansetron for hyperemesis suggested that HG itself, and not the drug, might be to blame for birth defects.
Back in Washington, D.C., there has been quiet movement on the larger issue of research and pregnancy. Bipartisan bills introduced this spring in the Senate and the House of Representatives would establish a task force on research specific to pregnant women and (in the case of the House legislation) require annual updates from the FDA. The FDA is scheduled to issue its own draft guidance entitled “Pregnant Women in Clinical Trials — Scientific and Ethical Considerations” later in the year.
The agency also has approved a new drug for morning sickness called Diclegis — basically, the long-abandoned Bendectin under a new name. Last year the American College of Obstetricians and Gynecologists revised its practice bulletin, urging doctors to prescribe Diclegis as the first line of defense against NVP and ondansetron only after weighing the benefits against the risks. But Diclegis is less powerful, more costly, and Smiley and her lawyers believe women are still being given ondansetron out of habit.
Recently, she saw an old friend at church who happened to be pregnant. “She said, ‘I’m having these really bad spells with nausea. It’s hard for me to get out of bed. It’s hard for me to go to work.’”
Smiley told her friend about Zaidan and everything her family had been through. “I was like, ‘Hey, whatever you do, I don’t know if there’s any truth to this, but please find something else to take.’”
Lyam David-Kilker was born on 24 October 2005, the second son of Michelle David and Miles Kilker of Bensalem, Pennsylvania. At birth he seemed like a normal, happy, healthy infant, but all that soon changed. His breathing was labored, and he became lethargic and lost his appetite. His parents took him to the doctors, who delivered devastating news. Lyam was born with multiple cardiac defects: a hole in his atrial septum, a hole in his ventricular septum, along with transposition of the great arteries—the same condition which afflicted Christiane and Amery’s son Daniel. Lyam required two open-heart surgeries and spent the first six months of his life in the hospital.
Shortly before conceiving, Michelle David had been prescribed Paxil for mild anxiety and occasional panic attacks, and she continued to take the drug throughout her pregnancy. After Miles Kilker heard a commercial message on television for the law firm linking Paxil to congenital heart defects, Michelle called the number and was referred to Sean Tracey, a personal injury lawyer from Houston.
During the trial, the plaintiff’s lawyers cited a couple of 2001 emails to GlaxoSmithKline from a woman (not Michelle David) who had taken Paxil while pregnant. The woman’s name was redacted from all court documents. The first email from her, dated 31 May, read:
“My name is [redacted]. I was diagnosed with panic disorder about four-and-a-half years ago. Since that time I’ve been taking Paxil, which is truly a miracle drug. I’ve been panic-free with this drug and have been able to go on with a normal life.
“I was married in October of 2000.My husband and I found out we were pregnant at Christmas time. I was so excited. I love children. The only problem is that I carried the baby to six months gestation and then had to have a termination.
“The doctors diagnosed my son with Truncus arteriosis. They said he would not lead a normal childhood and would most likely not make it through the open heart surgery that he would need as soon as he was delivered (if he was able to make it to that time). To say the least, I was absolutely distraught with this news.I thought this was something that I did, was 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. My husband and I are ready to try again to get pregnant in the next month or two. I am so nervous. I don’t want to stop taking my miracle pill. 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.
“Please contact me as soon as possible. I love everything this drug has done for me. I am so thankful that your company had this available for me.I just want to continue to have a normal life and have the child that I always wanted. Please contact me as soon as possible.
“Please don’t forget about me,Thank you.”
“Thank you for your inquiry. We are attaching a copy of our current product information for Paxil. Please review the section on use during pregnancy. 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. Because patient care is individualized, 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.
“Our drug information department is available to answer any questions your physician or pharmacist may have about our products. Your healthcare professional can call our drug information department at 1-888…”.
Congenital malformations associated with this drug
At that time, the prescribing information for Paxil made no mention of the number of reports of congenital malformations associated with this drug, and it was company policy not to tell doctors, patients, or pharmacists, either.
On 1 June, the mystery woman wrote again:
“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. 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 am in no way insinuating your product did this to my child. 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. I just want to start to try and get pregnant again soon. 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? Does anyone do studies like this?Please, any information you may give me would be great.Thanks again for your help.”
GSK responded to the mystery woman’s query by certified mail, asking her to sign a form authorizing the release of her medical records to GSK. The letter never reached her—it was returned as “undeliverable” by the US Postal Service. GSK apparently made no further efforts to communicate with her, although they did send a Medwatch report to the FDA, stating that “mother’s concurrent medications and medical conditions were not specified.” An internal GSK document, dated 13 June 2001, stated the link between Paxil and the cardiac defects suffered by the mystery woman’s unborn fetus was “almost certain.”
Lawyers for GSK argued that somebody must have checked the “almost certain” box by mistake. The jury didn’t buy it, and on 29 October 2009 awarded $2.5 million to Lyam Kilker.
Lyam survived, but hardly unscathed. For the rest of his life he will suffer from high blood pressure and diminished energy, and he will need repeat surgeries to replace the grafts covering the holes in his heart.
On 2 July 2012, the United States Department of Justice announced that GlaxoSmithKline had agreed to pay $3 billion to settle claims of illegal marketing of its products, including Paxil—the largest such payout in history. The same day the settlement was announced, the value of GSK shares rose 1.3%.
David Healy is a Professor of Psychiatry at Bangor University and the author of Pharmageddon, and he also testified as an exert witness at the Kilker trial. In a telephone interview he blasted SmithKline Beecham for not following up on early indications that paroxetine could cause birth defects. “They didn’t do what they ought to have done, do the kind of studies that they ought to have done.” He likened their attitude to that of tobacco company executives confronted with evidence of the harm their product could cause: “Let’s not look too closely at this.”
The mystery woman was later identified as Joanne Thomas, and she subsequently filed a wrongful death suit against GSK. On 27 November 2013, the Common Pleas Court of Philadelphia ruled against her on the grounds that the developing fetus (whom she called Ryan) had not reached the age of viability when the pregnancy was terminated. The certificate of fetal death listed Ryan’s gestational age as 21 ¬Ω weeks, whereas 3 days before the pregnancy was terminated, a cardiologist estimated Ryan’s age at 22 weeks. According to Pennsylvania law, a fetus is not considered “viable” until the age of 23 weeks.
Next: Part 4: “Patient safety is our highest concern”
Interesting article on the Paxil (seroxat) birth defect trials that GSK is trying to quash at the moment, particularly these parts-
“…The drugmaker also railed against evidence that lab notebooks from 1979 animal studies were destroyed in 1993, saying the claim “grossly distorts the regulatory practices in place at the time” and is “a manufactured controversy” likely to make jurors assume malfeasance….”
” GSK asked the judge to bar evidence about a 2012 plea agreement and three civil settlements; it pled guilty to one misdemeanor count of drug misbranding. This guilty plea carried no implication of fraud with it, the company said. And the misbranding had to do with Paxil’s use for patients under 18.”..
Law360, New York (January 24, 2017, 4:49 PM EST) — Jurors in an upcoming trial over birth defects allegedly caused by the antidepressant Paxil must not be told about drugmaker GlaxoSmithKline‘s alleged campaign to defraud the FDA, about destruction of study data or about its 2012 guilty plea on misbranding charges, the company insisted Tuesday.
The company filed a slew of motions seeking to box out evidence it said is irrelevant to mother Kathryn Kiker’s claims that taking the drug while pregnant caused her child’s ventricular septal defect, a serious heart problem. The trial is set for Feb. 21 in the Columbus, Ohio, courtroom of U.S. District Judge Edmund Sargus.
“GSK anticipates that plaintiffs will argue at trial that GSK committed ‘fraud on the FDA’ by not cooperating fully with, and by withholding information from, the FDA regarding adverse events, animal studies and/or clinical trials … so that the FDA did not undertake regulatory action with regard to Paxil,” the company said. But the claims “are incorrect, irrelevant and inadmissible,” it said. “Furthermore, the U.S. Supreme Court has held that FDA — not a private plaintiff — has exclusive authority to police disclosures made to [the] FDA.”
The drugmaker also railed against evidence that lab notebooks from 1979 animal studies were destroyed in 1993, saying the claim “grossly distorts the regulatory practices in place at the time” and is “a manufactured controversy” likely to make jurors assume malfeasance.
And in another motion, GSK asked the judge to bar evidence about a 2012 plea agreement and three civil settlements; it pled guilty to one misdemeanor count of drug misbranding. This guilty plea carried no implication of fraud with it, the company said. And the misbranding had to do with Paxil’s use for patients under 18.
Even as information about character, the plea deal is not usable, the company said.
“Evidence regarding felonies and any crime whose elements require proof of a dishonest act or false statement may be admissible for impeachment. GSK’s plea to no-intent, strict-liability misdemeanors under the FDCA is inadmissible for impeachment purposes because it does not fall within either category,” it said.
And it requested oral argument on another motion seeking to bar evidence about other lawsuits, investigations or media reports.
In October 2015, an Ohio federal judge ruled that GSK must face the suit because the mother successfully pled fraud.
U.S. District Judge Edmund Sargus denied GlaxoSmithKline LLC’s motion for judgment on the pleadings, rejecting its argument that Kiker’s claims accrued in September 2005, when the company told the medical community about Paxil’s links to birth defects, and are thus abrogated by the Ohio Product Liability Act, which was amended in 2005 and curtailed common-law liability claims in the state.
But the judge sided with Kiker’s argument that her claims accrued when her child, referred to as C.S., was born in 2001.
The judge said that a provision in the 2005 Tort Reform Act includes a discovery rule so that a bodily injury claim may be extended to a date when it was reasonable for the injured party to have discovered her injury was related to a product. The judge also found that the fraud allegations in Kiker’s proposed amended complaint were sufficiently particular, and granted her leave to file the amended complaint.
“At the time Paxil was prescribed to Ms. Kiker, GSK knew … that Paxil was associated with a significant increased risk of cardiac birth defects in babies,” Kiker said. “Other studies showed that increased levels of serotonin, the primary human substance affected by Paxil, had profound effects on the prenatal cardiac development of study animals.”
Despite knowing these risks, she said, GSK suggested Paxil was safer than other available selective serotonin reuptake inhibitors, or SSRIs, and misled the medical community as to its safety. Kiker said GSK did not begin to inform doctors of the risks until September 2005, when third-party research showing the association was released.
The entire time the drug has been on the U.S. market, federal regulations have required stronger warnings in the presence of evidence of a birth-defect link, Kiker said. These FDA regulations specifically state that the link need not be proven and that the company can issue the warning without agency approval.
Kiker is represented by Benjamin Anderson of Anderson Law Offices LLC and Bryan Aylstock, James Barger, Bobby Bradford, Roger Cameron and R. Jason Richards of Aylstock Witkin Kreis & Overholtz.
Law360, Boston (August 29, 2016, 5:06 PM EDT) — GlaxoSmithKline LLC had enough purposeful contacts with Illinois during clinical trials for the antidepressant Paxil for it to face claims from out-of-state residents that the company failed to warn that the drug could cause serious birth defects, a state appeals court ruled Friday.
The First District Appellate Court of Illinois, Fifth Division, ruled that the standard for a showing that a defendant’s conduct was “arising from” its contacts with the state was “lenient and flexible,” giving the state courts jurisdiction over the pharmaceutical giant. The decision in an interlocutory appeal upholds the trial court’s denial of GSK’s dismissal bid.
“In light of the lenient and flexible ‘arising from’ and ‘related to’ standard, plaintiffs meet the low threshold of a prima facie showing that their claims arose from defendant GSK’s Paxil trials in Illinois,” the appeals court said.
In the suit, eight minors from six states — Illinois, Florida, Colorado, Virginia, Michigan and Wisconsin — said that they suffered catastrophic birth defects because their mothers were taking GSK’s Paxil. The label failed to warn them of serious birth defects that the drug could cause, the plaintiffs said, and that was the result of inadequate clinical trials, 18 to 21 of which occurred in Illinois via 17 Illinois doctors. That meant that the claims arose directly out of or were related to GSK’s purposeful contacts with Illinois, the plaintiffs argued.
GSK argued that Illinois did not have jurisdiction over the out-of-state plaintiffs.
“GSK is disappointed by the court’s decision and is considering its options,” the company said in an emailed statement Tuesday.
Tor Hoerman, whose firm represented the plaintiffs, said in an emailed statement: “This decision is entirely in line with existing precedent of the Illinois Supreme Court and Appellate Court. … Drug makers who conduct inadequate or manipulated clinical trials in Illinois should not be surprised that they can be sued in Illinois for that conduct.”
In trying to have the suit dismissed as to the out-of-state plaintiffs, GSK said that its clinical trials occurred in 44 states and foreign countries, too attenuated for personal jurisdiction in one state where it’s not headquartered. Its alleged acts or omissions in Illinois were not the “but for” cause — in other words, GSK said, the plaintiffs couldn’t show that the harm would not have occurred but for what GSK did in Illinois.
In addition, GSK argued, the plaintiffs weren’t study subjects there, and the out-of-state plaintiffs didn’t take Paxil or suffer injuries in Illinois.
The children and their mothers argued that GSK had meaningful contacts with Illinois through its clinical trials of Paxil, during which they said it failed to track 18 pregnancies, one of which resulted in a heart defect. According to Friday’s decision, GSK employs 16,323 people in the U.S., including 217 who reside in Illinois, and from 2000 to 2006, GSK had between 79 and 121 employees marketing Paxil in Illinois.
They did not have to prove that any act was committed in Illinois, but just make a prima facie showing, the defendants said.
In a ruling Friday, the appeals court sided with the plaintiffs.
“The quality of defendant GSK’s relationship with Illinois can hardly be characterized as random, attenuated or the like; the contacts with Illinois, over the course of two decades, were purposeful and directed,” the appeals court ruled.
The plaintiffs, and the judges, used some of GSK’s own statements to show that the case could continue. In a declaration, GSK said that the principal Paxil investigators had “little or no input into or control over the study design protocol or analysis of the aggregate data collected from all study sites.”
“As plaintiffs argue, the word ‘little’ invites the inference that the physicians had some degree of input into, and control over, the clinical trials, or else the word would have been omitted,” the appeals court said. Absent further guidance in the record, we ‘resolve in favor of the plaintiff any conflicts in the pleadings and affidavits.’”
Judges Robert E. Gordon, Bertina E. Lampkin and Eileen O’Neill Burke sat on the panel for the First District.
“We are deeply grateful for the excellent medical care our daughter received,” stated Dulce Morga. “But the loss of Sarah will be a pain we carry with us for the rest of our days. We hope our lawsuit helps to alert other women to the issues with this drug.”
Zofran is a potent drug developed by GSK that was approved by the U.S. Food and Drug Administration to treat only patients afflicted with the most severe nausea imaginable – nausea suffered as a result of chemotherapy or radiation treatment. GSK nevertheless marketed Zofran “off-label” as a safe and effective treatment for the very common side effect of a normal pregnancy – pregnancy-related nausea and vomiting – otherwise known as “morning sickness.”
In 2012, GSK pled guilty to criminal charges filed by the U.S. Department of Justice for its off-label promotion of certain prescription drugs, including Zofran, for uses never approved by the FDA. Zofran, however, continues to be widely prescribed to pregnant women across America to treat morning sickness even though it was never approved for this use.
Ms. Morga and Mr. Ramirez’ daughter was born in late 2014 with congenital heart defects, including severe Epstein’s anomaly of the tricuspid valve. Per her doctor’s notes, she was born with an enormous heart with a very large atrialized right ventricle that was not functioning. She underwent open heart surgery when she was just five days old, and did not survive the trauma and passed away in her mother’s arms five days later.
“Despite having received hundreds of reports of birth defects associated with Zofran and continuing strong sales to pregnant women, GSK has not performed any clinical studies on the safety or efficacy of Zofran for treating morning sickness,” stated London, counsel for Mr. Ramirez and Ms. Morga. “Moreover, GSK has not updated Zofran’s labeling to warn mothers and physicians that epidemiology studies report an increased risk of birth defects in infants exposed to Zofran during pregnancy. Recent studies report that a mother exposed to Zofran had greater than doubled risk of having a baby with a heart defect as compared to a mother who did not ingest Zofran during pregnancy.”
The lawsuit was filed November 13, 2015 in federal court in the Central District of California. The lawsuit alleges claims of negligence, strict products liability, intentional misrepresentation, concealment, negligent misrepresentation, breach warranty, and violations of California law. Mr. Ramirez and Ms. Morga seek compensatory and punitive damages from GSK.
Published: 23:53 GMT, 8 July 2015 | Updated: 23:57 GMT, 8 July 2015
Two of the most-commonly prescribed antidepressants increased the risk of some birth defects by up to three and a half times
Women who take certain antidepressants during pregnancy are more likely to have a baby with a birth defect, research suggests.
Two of the most-commonly prescribed antidepressants – fluoxetine, sold under the brand name Prozac, and paroxetine, sold as Paxil or Seroxat – increased the risk of some birth defects by up to three and a half times.
Problems include heart defects, brain problems and irregular skull shape.
Experts stressed that the absolute risk is still small – heart defects among babies whose mothers took paroxetine, for example, increased from just 10 per 10,000 births to 24 per 10,000.
But the findings highlight concerns that the increasing use of antidepressant drugs could be having a detrimental effect on patients and their children.
The findings, published last night in the British Medical Journal, come after NHS figures released this week revealed that the use of antidepressants has nearly doubled in the last decade, from 29million prescriptions in 2004 to 57million last year.
Paroxetine and fluoxetine are among the most commonly prescribed, between them accounting for 8million prescriptions in 2014.
British experts last night insisted that antidepressants remain important – and that harm is far more likely to befall a baby if a depressed or anxious mother stops taking their medication.
Researchers in the US focused on selective serotonin reuptake inhibitor (SSRI) antidepressants, which they said are increasingly being used by women during pregnancy.
The team said that while they found reassuring evidence for some types of SSRI drugs, others significantly increased the chance of a baby being born with a defect.
Share this article
The research, led by the National Centre on Birth Defects and Developmental Disabilities in Atlanta, Georgia, looked at the health records of 28,000 pregnancies between 1997 and 2009.
They recorded use of the SSRI drugs citalopram (Celexa or Cipramil), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Seroxat or Paxil), and sertraline (Zoloft) at least once in the period from one month before conception through to the third month of pregnancy.
The two most commonly used SSRI drugs in England – citalopram and sertraline which together account for 22million prescriptions – were not associated with any increase in birth defects.
But fluoxetine and paroxetine – the third and fourth most widely used SSRIs – were linked to a significant increase in problems.
Fluoxetine was linked with heart wall defects and irregular skull shape.
But experts have tressed that the absolute risk is still small – heart defects among babies whose mothers took paroxetine, for example, increased from just 10 per 10,000 births to 24 per 10,000
Mothers who took paroxetine were more likely to have babies with brain and skull formation problems and abdominal wall defects.
The chance of brain and skull problems associated with paroxetine increased from two per 10,000 to seven per 10,000, and for heart defects from 10 per 10,000 to 24 per 10,000.
The authors wrote: ‘Although our analysis strongly supports the validity of the associations that were observed, the increase in the absolute risks, if the associations are causal, is small.
‘Continued scrutiny of the association between SSRIs and birth defects is warranted, and additional studies of specific SSRI treatments during pregnancy and birth defects are needed to enable women and their healthcare providers to make more informed decisions about treatment.’
But Dr Michael Bloomfield, a clinical lecturer in psychiatry at University College London, said that doctors in the UK generally prescribe lower doses of psychiatric medicines to patients than in the US and warned that no one should stop taking treatment without talking to their doctor first.
However the findings highlight fears the increasing use of antidepressants could be having a detrimental effect
He added: ‘Whilst common, depression can be a potentially life-threatening illness. Any decision around treatment in pregnancy needs to weigh up the potential small risks of birth defects against the benefits of treatments including helping a mother get better from depression.
‘In addition, there is evidence to suggest that a baby whose mother had depression during pregnancy may be more likely to have mental illnesses themselves during later life.’
Dr Patrick O’Brien, spokesman for the Royal College of Obstetricians and Gynaecologists, added: ‘Our advice for pregnant women suffering with depression would be that generally the benefits outweigh the risks, however, all pros and cons should be discussed and weighed up by a woman, together with her obstetrician.’