The IUD that gives women options

Posted by on Oct 5, 2017 in IT News | 0 comments

The IUD that gives women options

In a Taupe-Walled exam room at the Women’s Community Clinic in San Francisco, lead clinician Lisa Mihaly plucks a small laminated card from a cabinet. Tethered to the card are three T-shaped IUDs, or intrauterine devices—forms of birth control that are, as the name implies, inserted into a woman’s uterus to prevent pregnancy for up to 12 years. Mihaly points to each device like friends in a group photo: Paragard, with its thin bands of copper coiled around a white plastic trunk and two arms at attention; Mirena, the first hormonal IUD available in the US; and Skyla, an IUD designed for women who have never had children. But there’s one option missing, Mihaly says: a newer model called Liletta.

Liletta, which arrived in the clinic’s inventory this summer, is a small device that manufacturers hope will make a big difference. Public clinics pay a wholesale price of $336 to $400 for each of the IUDs on Mihaly’s card. Add in doctor’s visits for placement and the total cost can exceed $1,000. Liletta’s manufacturer hopes to see a wholesale price for public clinics as low as $50.

Price point matters, possibly more than ever before. Under the Affordable Care Act, women rarely pay full price for an IUD because of provisions requiring insurers to fully cover at least one option from each of the 18 FDA-approved birth control methods. But when Donald Trump took office on a promise to repeal the ACA, IUD insertion rates soared as women sought long-term contraceptive solutions.

Though the ACA is safe for now, The Wall Street Journal reported in August that the Trump administration is planning to roll back the birth control requirement, allowing employers to demur based on religious or moral objections. And affordable, accessible birth control will always be a public health concern. In April, Trump signed a law giving states more freedom to restrict their spending of federal money from the Title X program, which supports the clinics that care for women with Medicaid, or no insurance at all, at lower cost.

Politics and pricing aside, the IUD has experienced something of a revival in the United States. For years a negative narrative dogged the devices—in the 1980s, the Dalkon Shield caused infections and even deaths. But new, safe models, including Paragard and Mirena, made it to market and the mainstream. Since 2002, the number of American women using IUDs has roughly doubled every four years. But it remains low, internationally speaking—just 8 percent of reproductive-age American women use an IUD, compared to 20 percent of Belgians and nearly 70 percent of South Koreans—but the trend continues upward.

And why not? The IUD is among the most effective contraceptives, preventing pregnancy in 99 percent of women who use it over the course of a year. The levonorgestrel in hormonal IUDs stops ovulation or thins the uterine lining, so eggs are less likely to implant, and the physical presence of a foreign object often thickens cervical mucus enough to stop sperm. Plus, they’re inserted once and last for years. “There’s no room for error. You can’t forget to take it, or forget to get the resupplies,” says Cynthia Harper, a reproductive health researcher at UCSF. Just set it and forget it.

While many women have now heard of IUDs, few know about Liletta—partly because it’s produced by Medicines360, a San Francisco nonprofit edging into a product category long dominated by Bayer, the pharmaceutical giant that makes three of the four hormonal IUDs available in the US. When Mirena received FDA approval in 2000, there wasn’t a single other hormonal IUD available in the US. It remained the only option until 2013, when Bayer released Skyla, a model specific for nulliparous women. And in 2016—a year after Lilleta earned FDA approval—the company released its third hormonal IUD, Kyleena.

Bayer’s IUDs netted the company $900 million in the US in 2016, and they’ve been among the company’s 15 best-selling drugs for the past decade. It’s a big business—and it doesn’t look like that will change anytime soon.

Bayer has created a suite of IUDs that target women with different birth control needs: Skyla has a three-year lifetime and lower hormone levels, while Mirena and Kyleena are approved for five-year use with slightly higher doses of hormones. And Skyla and Kyleena’s smaller size is aimed at women who haven’t had children.

The differences aren’t strictly clinical, though. The timing of Bayer’s product releases also allowed the company to keep its own patent-protected devices on the market. Drug patents typically last 20 years from the day a company files its application. With IUDs specifically, which bundle a drug (the body of the IUD) with a device (the inserter a doctor uses to place it), there are two ways to restart the patent clock: bring a new IUD through clinical trials or design a new inserter.

So in 2010, Bayer put two new IUDs—then experimental LCS16 and LCS12, now Skyla and Kyleena—into a clinical trial in Europe, North America, and South America. The company could have run each trial for five years so the new offerings would match Mirena’s efficacy, but it finalized Skyla’s data at three, releasing it in 2013, before Mirena’s patent ran out in 2015. Kyleena stayed in the same trial for two more years, receiving FDA approval in 2016.

Bayer has made other moves to maintain its market dominance. In 2014, the year before Mirena’s first patent expired, the FDA established guidelines for studies to approve a generic form of the device, as it does for many drugs. The agency later withdrew the guidelines, but proposed spending up to $250,000 in grant money for researchers to find ways to evaluate drug equivalence of generic versions of Mirena. In response, Bayer submitted a citizen petition to the FDA, a 10-page statement urging the agency to require that proposed generics undergo comprehensive clinical testing rather than lab experiments to prove equivalence. The company submitted the petition one day before Mirena’s patent expiration date.

Citizen petitions allow ordinary people to have input on health policy, but drug companies have historically employed them to discourage generic drug production, says Michael Carrier, an intellectual property lawyer at Rutgers Law School. The petitions are all carefully considered—safety concerns are nothing to ignore—but the FDA ultimately denies many of the requests that large companies submit. “If it really were about safety,” Carrier says, “then why is the company waiting until the very end?”

Bayer’s petition mentions that the company has been “waiting patiently” for the FDA to update the guidelines for testing generic forms of the Mirena IUD, and the long timeline has led them to submit a citizen petition. The FDA hasn’t issued a final response to Bayer’s citizen petition, and the agency keeps any inquiries about making a generic product confidential. Bayer did not respond to questions by press time.

Like Mirena, Liletta doesn’t have patent protection on its IUD body. And Liletta is closely modeled after the Mirena, although technically it’s not a generic. It’s a hybrid new drug, different enough from Mirena to stand on its own but similar enough to simplify the clinical trials that earned it FDA approval.

Liletta’s IUD body was developed in the late 1990s, when Mirena was first approved in Europe. Jean Michel Foidart, an ob-gyn at the University of Liege, in Belgium, loved the concept of the hormonal IUD, but not the cost. The IUD itself is just a tiny piece of plastic, less than a tenth of a gram of hormones, and two small strings for removal. So Foidart figured he and his lab could create a much cheaper alternative. They mimicked Mirena’s T-shape and dosed their model with the same hormone, levonorgestrel. An equally effective IUD with a lower price, he hoped, would provide better access to effective birth control.

There appeared to be a need for better and more reliable contraception in the US. In the mid 2000s, American women were largely relying on less-effective birth control methods, says Harper, the health researcher. Half of US pregnancies were unplanned. So in 2009, an anonymous donor—since identified as the Susan Thompson Buffett Foundation, which Warren Buffett runs in honor of his late wife—funneled $70 million to Medicines360 to get a lower-cost IUD available in the US.

It was an ambitious undertaking for the tiny company. In 2009, the entire team of Medicines360 consisted of Victoria Hale and then COO Ahvie Herskowitz. They licensed Foidart’s IUD for distribution in the US and the developing world, changed the name from Levosert to the more marketable Liletta, and inworked with the pharmaceutical company Watson (which has since become a part of Allergan) for manufacturing.

Having a deep-pocketed benefactor gave Hale and her team the freedom to spend time and money on development. Andrea Olariu, who Medicines360 brought on as VP of clinical affairs in 2011, first called clinicians to understand where they needed help—professors at medical schools, MDs, and nurse practitioners. The final version of Liletta, they hoped, would be more affordable, and a better product too.

No one they spoke to raised many complaints about the IUDs. Instead, their feedback focused on insertion. To insert an IUD, a doctor or a nurse uses a wandlike gadget to guide it. A small tube at one end holds a flattened device, so when a nurse threads the tube into the cervix, then nudges the IUD upward, it unfolds into the uterus. The procedure takes just a few minutes, but speed doesn’t mean precision. Clinicians found it hard to tell whether an IUD had fully exited an inserter, and complained that straight, rigid guiding tubes didn’t accommodate the diverse geometries of uteruses. So Olariu worked alongside an engineer, Robert Deckman, to design and test 10 or so inserter prototypes. The finished product is about a foot long, with a thin handle at one end and the floppy tube that contains the IUD at the other. “It makes like a little dome,” says Jessica Grossman, who took over as Medicines360’s CEO in 2015, “so when you insert it into the cervix it doesn’t cause trauma, and then you deploy the IUD in the uterus by pulling down on this,” she says, pressing a small slider down with her thumb. The IUD exits the insertion tube with an audible click—so a nurse, who can’t see what’s happening, knows insertion took place.

With a finalized device in hand, Medicines360 was ready for the trickiest part of its process: clinical trials.

In 2009, Olariu cast a wide net as she began to enroll patients in Liletta’s phase 3 safety trial. In 2000, Mirena was approved based on data from Finland and Sweden, and she hoped to include a wider range of patients in Medicines360’s trial in America. “Our goal was, as much as we could, to mirror the US population,” Olariu says.

They extended their age range to include women between 16 and 45, rather than the typical 18 to 35 demographic of contraceptive studies, to recruit more women who had never given birth. And by enrolling 2,000 women from 27 cities around the country, their enrollment reflected the US census pretty closely. Roughly a quarter of participants were overweight or obese women, who often are excluded from these trials as researchers are uncertain of how weight might affect response to hormones.

Liletta received FDA approval for three-year use in February 2015, two months after Bayer submitted its citizen petition to require stringent testing for any generic versions of Mirena. The unresolved petition never caused Liletta any trouble, as it’s a unique drug—the Liletta IUD releases a slightly different amount of hormone per day (18.6 micrograms to Mirena’s 20), and has a custom-designed inserter.

In rolling clinical trials, Liletta has now been approved for four years of contraception, and Medicines360 will submit their data for five-year approval soon. More than 600 clinics stock Liletta, and in two years they’ve provided nearly a hundred thousand patients with IUDs, Grossman says. “The difference with Liletta is that it’s much cheaper than the other IUDs,” says Kristyn Brandi, an ob-gyn from the American College of Obstetricians and Gynecologists.

With more options becoming available, the American Congress of Obstetricians and Gynecologists maintains that IUDs are one of many good birth control options. There are clearly differences between hormonal and copper IUDs, and even some differences in lower and higher doses of levonorgestrel. But smaller sizing, one of the marketing points for Bayer’s latest releases, might not make as much of a difference for the majority of women. “Some women like the idea that a smaller IUD might be less painful on insertion, but in general all the IUDs are well tolerated,” Brandi says.

Liletta’s approval might open a faster, easier, and cheaper route to an IUD, particularly for women who are uninsured, as many of the patients who Lisa Mihaly sees are. But the women sitting in the Women’s Community Clinic waiting room, like other women around the country, might still lean toward the other options. Say your sister has Mirena, and your best friend uses Skyla, and you see an ad for Kyleena as you’re flipping through a magazine while you wait. It’s going to be hard to opt for the unfamiliar Liletta. And Medicines360’s nonprofit budget doesn’t provide for an advertising campaign like the one Bayer once used to offer a free yoga class alongside ‘Break Up With The Pill’ messaging at Canadian universities.

Since Liletta’s initial approval in 2015, Mihaly still hasn’t had a patient ask directly for a Liletta IUD. But the devices are in stock, and she’s trained to place one as soon as someone is interested. “I’m excited that Liletta exists, and that there’s another option,” she says, “because we have, really when you think about it, so few.”