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FDA approved NuvaRing despite experts' safety concerns
NuvaRing

FDA approved NuvaRing despite experts' safety concerns

Merck & Co. Inc. has agreed to pay $100 million to settle thousands of lawsuits and claims over birth control ring.

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At age 17, La Monica Greene began using a novel contraceptive device. The St. Louis teenager had obtained a prescription for NuvaRing — a vaginal, once-a-month birth control ring.

Several weeks later, she died.

Her mother, Monica Greene, filed a wrongful death lawsuit against the manufacturers and sellers of NuvaRing, which include Dutch and U.S. companies now owned by New Jersey-based Merck & Co. Inc.

According to the lawsuit, the teen began using NuvaRing in May 2009. A few weeks later, she began to experience chest pains and shortness of breath. On June 21 of that year, the suit alleges, she suffered a blood clot in one of her lungs resulting in her death.

Monica Greene, who works for the city of St. Louis, said her daughters La Monica and Stephanie dreamed of being veterinarians and opening an office together. The two brought stray cats, birds and dogs to the house to nurse them.

La Monica “was active in church. She was sweet and outgoing and loved to help,” her mother said. “I wanted my kids to be loving, to have a heart. I didn’t want them to be cold-blooded.”

Her daughter’s death, she said, “just blew all of us away.”

Greene’s case is one of more than 1,850 lawsuits filed nationwide against the makers of NuvaRing since 2007, including about a dozen cases brought by Missouri residents. Most of the lawsuits have been consolidated in federal court in Missouri; none has gone to trial.

Last month, Merck agreed to settle all NuvaRing cases nationwide for $100 million. Of that amount, an estimated 30 percent to 40 percent would pay attorneys fees and expenses. There are about 3,800 eligible participants in the settlement plan, which includes not only lawsuits already filed but also claims not filed in court.

U.S. District Judge Rodney Sippel has called it “a fair resolution,” but the agreement is contingent on 95 percent of the eligible claimants opting in to the program. The deadline is March 10.

According to the plaintiffs, NuvaRing was designed and produced without adequate testing and study. But the developers and makers of NuvaRing deny any wrongdoing. They say the vaginal ring is as safe or safer than birth control pills that were already approved for the U.S. market. And they stress that deep blood clots are rare events among NuvaRing’s users.

“Nothing is more important to Merck than the safety of our medicines and vaccines and the people who use them,” Merck said in a written statement. “We stand behind the research that supported the approval of NuvaRing, and our continued work to monitor the safety of the medicine.”

NuvaRing was approved by the Food and Drug Administration in 2001 after several FDA investigators, doctors and managers voiced concerns about its potential for causing blood clots. Since 2002, global sales of NuvaRing have totaled more than $3 billion. NuvaRing is marketed in 50 countries.

The NuvaRing litigation revolves around the issue of how drugmakers account for “outliers” — the small percentage of customers who use a federally approved drug or device and allegedly suffer serious harm.

According to the lawsuits, the drugmakers failed to warn doctors and patients about NuvaRing’s risk of blood clots because the product’s labeling did not fully reflect the data from clinical trials.

Medical studies have linked Nuva-Ring to life-threatening injuries such as strokes, heart attacks, deep vein thrombosis (a blood clot that forms in a vein that is not externally visible), and pulmonary embolism (when a blood clot breaks free and lodges in one of the lungs).

Merck, however, said that timely information about NuvaRing’s risks has been provided to consumers, doctors, researchers and regulators.

Advertisements for NuvaRing tout its convenience — compared with taking a daily birth control pill. More than 44 million prescriptions for NuvaRing have been written.

Still, the product’s trail of alleged injuries is lengthy.

Sarah M. Jenn, of Fenton, sued the makers of NuvaRing in 2007 on behalf of her mother, Dana Jenn, who was 40 years old at the time of her death.

According to the lawsuit, Dana Jenn began using NuvaRing in June 2005. On the evening of July 15, 2005, she experienced severe shortness of breath while on a treadmill and collapsed. Attempts to revive her failed. She died hours later from a pulmonary embolism.

Sarah Jenn, now a resident pediatric physician in San Antonio, was 19 when her mother died.

“I had a pretty good childhood growing up and for the first time in my life I wanted time to go backwards rather than forward,” said Jenn, noting that her mother was a healthy, long-distance runner with no history of blood clots. “The past was more inviting than the future.”

In addition to wrongful death cases, many of the NuvaRing lawsuits say the vaginal ring caused life-threatening injuries and chronic conditions. These suits call for damages including disability, lost earnings, pain, suffering and mental anguish.

Janis Mitchell-McGuire, of East St. Louis, filed a lawsuit in 2008. According to her complaint, she began using NuvaRing at age 28 in February 2004. She suffered a massive pulmonary embolism in August of that year, which resulted from blood clots throughout her body. Mitchell-McGuire was hospitalized twice for her condition, and told to take anticoagulants to prevent further blood clots.

“No one’s willing to accept blame or to admit blame, but my life has been turned upside down,” Mitchell-McGuire said. “For anyone who takes this drug, read the label and know your risk, because it can cause lifelong damage.”

APPROVED BY FDA

NuvaRing is a flexible, plastic ring that is inserted monthly in the upper vagina and releases a combination of hormones — progestin and ethinyl estradiol — to prevent ovulation.

It is marketed by Organon USA Inc. and Organon Pharmaceuticals USA Inc., both New Jersey companies, and Organon International Inc., which is headquartered in the Netherlands. These firms, which are currently owned by Merck, are former subsidiaries of Akzo Nobel NV, a Dutch chemical giant. Schering-Plough Corp., a New Jersey drugmaker, purchased the Organon firms in 2007. Two years later Schering-Plough was acquired by Merck.

To win FDA approval, Akzo Nobel submitted an application for NuvaRing in December 1999, a month after it received a U.S. patent. The FDA approval process, which weighed NuvaRing’s risks and benefits, entailed two years of negotiations.

The drugmaker submitted data from two, large-scale clinical research trials from the United States and Europe to show that NuvaRing was “safe for use” and would prevent pregnancy. FDA officials identified potential risks.

In an Oct. 6, 2000, memo, Dr. Daniel Davis and Dr. Gerald Willett — FDA medical officers who reviewed NuvaRing’s application — wrote that “thromboembolism,” or deep blood clots, were “the most controversial safety issue.”

They noted that a 26-year-old woman who had participated in a NuvaRing clinical study for “only eight days” developed a severe blood clot in her left lower leg. The woman’s use of NuvaRing was immediately discontinued, and she was placed on anticoagulants for 14 weeks.

According to Davis and Willett, two additional women in the study experienced less serious blood clots and needed to discontinue their use of NuvaRing. “Due to lack of follow-up it is difficult to draw meaningful conclusions from these two subjects,” the reviewers said.

Davis and Willett recommended FDA approval of NuvaRing, but they objected that the drugmaker’s proposed label did not include specific safety data from the clinical trials. Adding such data to the label’s warning section, they said, “will help to better inform both health care providers and consumers about this new delivery system for combination hormonal contraception.”

In a Dec. 22, 2000, memo, Dr. Florence Houn — an FDA director — concurred with the staff recommendation to approve NuvaRing once doctor and patient labeling issues were resolved. The drugmaker agreed to undertake four post-marketing studies, but none involved blood clots.

Also on that date, Dr. Susan Allen — an FDA director — signaled her intention to recommend approval of NuvaRing pending final agreement on labeling issues and post-marketing studies. One labeling issue cited by Allen: the FDA’s recommendation to shorten the out-of-refrigeration storage period for NuvaRing “to reduce the likelihood of ‘burst hormone’ release upon vaginal insertion of the product.”

According to plaintiffs’ medical experts, NuvaRing produces spikes of higher levels of estrogen that are not accompanied by similar spikes of progestin. Estrogen has been linked to higher risks of blood clotting.

NuvaRing’s novel delivery method increases the risk of developing a life-threatening blood clot, the plaintiffs allege. Unlike birth control pills, the hormones within the ring are absorbed into the bloodstream through the vaginal wall.

In her memo, Allen said that NuvaRing’s label would have the same warning on blood clot risk as that found in FDA-approved third-generation birth control products such as Yaz and Yasmin. Studies had reported that these pills are associated with a two-fold increase in the risk of blood clots, compared to second-generation birth control pills.

Allen left the FDA in 2006. Months later, she began performing consulting work for Organon. She did not return phone calls seeking comment.

Kristine Kraft, a St. Louis lawyer suing Merck, said Organon “lobbied hard” against the inclusion of any mention of deep blood clots — the most serious side effect — in its labeling. She also said the FDA did not order sufficient studies to determine if NuvaRing’s unique delivery system presented a greater risk to women than birth control pills.

“The company did not act responsibly,” Kraft said.

Organon executives successfully persuaded the FDA there was no need to mention the case of a clinical trial participant’s severe blood clot in NuvaRing’s warning label.

“We should really try to get it out of the text,” Wim Mens, of Organon’s regulatory affairs division, wrote in an email to colleagues regarding the FDA’s proposed version of the label.

“What are the chances that this (deep vein thrombosis) section can be removed altogether?” asked David Stern, an Organon marketing manager, in a December 2000 email.

In the FDA’s final medical office review, Davis and Dr. Dena Hixon wrote Sept. 17, 2001, that the potential increased incidence of deep blood clots with NuvaRing “remains the major safety concern. … No safety data exists on long-term — more than 13 months — of NuvaRing, and it is unknown whether the increased incidence of VTE (deep blood clots) will be found with NuvaRing use.”

Product labels for patients and doctors, they said, should reflect the increased risk of blood clots, and post-marketing studies should determine whether NuvaRing was causing serious adverse events such as blood clots.

Andrea Fischer, an FDA spokeswoman, said that Davis, Willett and Hixon were unavailable for comment. Houn, now a vice president for regulatory matters at New Jersey-based Celgene Corp., a biotechnology company, was also unavailable for comment.

MARKETING CAMPAIGN

After winning FDA approval for NuvaRing in October 2001, Organon launched a big marketing push to sell the contraceptive.

Organon sponsored studies from 2003 to 2007 to gauge the acceptability of NuvaRing among teens and university students. One study, for instance, asked whether teens and young women would prefer NuvaRing to oral contraceptive pills after having tried both methods.

NuvaRing magazine ads proclaimed “Let Freedom Ring” and featured a group of synchronized swimmers posing as birth control pills. NuvaRing television commercials starred actress Hayley Marie Norman.

But soon after NuvaRing hit the market, concerns grew about its safety. The FDA began receiving hundreds of “adverse event reports” of complications among women.

Dr. Suzanne Parisian, a former FDA official and expert witness for the plaintiffs, said that Organon did not conduct adequate safety studies before regulatory approval, played down NuvaRing’s risks in its marketing, failed to conduct proper post-marketing studies on NuvaRing’s side effects, and did not voluntarily update its labeling as reports of serious blood clots increased.

In 2005, the FDA ordered the drugmaker to change its warning label to indicate that women with a history of heart disease, blood clots and hypertension should not use NuvaRing due to their increased risk of developing adverse reactions.

NuvaRing continues to be prescribed by doctors. In 2012, Merck reported NuvaRing sales of $623 million.

Jenn said the wrongful death case she filed on behalf of her mother had a purpose.

“This lawsuit wasn’t about punishing anyone or any kind of personal gain,” she said. “I thought it was important to add her voice to all the other women who had a bad outcome from this drug. If this was happening to lots of women, it needed to be heard.”

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