Editor's note: On October 17, Evofem announced a merger with publicly traded Neothetics. The combined company will be called Evofem Biosciences. Saundra Pelletier will be the CEO.

When your job involves trying to bring to market what could be the biggest breakthrough in birth control since the pill, you keep your mornings predictable. Every weekday, Saundra Pelletier gets up at 4:30 a.m., trying not to wake her 10-year-old son while she slips into her workout gear, which includes a sweatshirt with the word bullshit printed on the left shoulder. By 5, the 48-year-old single mom--who lives about a half hour from the San Diego offices of her company, Evofem Bio­sciences--is on the phone, often with her investors in London. At 5:30, still on the phone, Pelletier exits her garage with a quick nod to the nanny, who is on her way in. Half an hour later, she's at either CrossFit or Fitwall, where she can work all the major muscle groups in 40 minutes. As the cool-down session begins, Pelletier bolts, already en route to her next stop and a triple soy latte from Starbucks. Since there are no locker rooms at either gym, she swings back home--the phone automatically clicking over to a waterproof speaker in her bathroom--to clean up. Back in her car, she dictates emails to her assistant, until arriving at the office by 8:30. "We get quite a lot done, actually," she says.

But there's always room for improvement. When Thomas Lynch, the chairman of Evofem's board and the head of Ireland's largest hospital group, asked what he could do to thank Pelletier for her work as CEO--aside from stock--she responded by asking that a shower be installed at the office. "So what you're telling me," he said, "is you want something that lets you work more?" She did. (Lynch obliged.)

In Pelletier's list of priorities, her morning routine comes third, after only her son and her companies. That leaves her mom and her fiancé (the founder of apparel company Athleta) duking it out for fourth place.

Perhaps the reason Pelletier is so wedded to early-morning certainty is not because of any deficiencies in her relationships with her loved ones, but because her company is dealing with a level of uncertainty that most startups, and their founders, will never contend with. "We've had a significant amount of failure," Pelletier concedes. That uncertainty may explain why, when everyone in her son's class at school had to say what their parents would like as a holiday gift, her son replied: "My momma would like a dirty martini."

Saundra Pelletier is running a drug startup and a nonprofit to fulfill her mission of bringing better contraception to women around the world.
CREDIT: Joyce Kim

For Pelletier to achieve Evofem's goal of becoming a global leader in women's health, for its investors to see a return, and to potentially affect women from San Diego to Malawi, she needs to successfully commercialize what is now the company's only product: Amphora, a new form of contraceptive gel that has yet to be approved by the U.S. Food and Drug Administration.

Innovations in contraception, at least in the U.S., have in recent years been few and far between. Yet, according to the Guttmacher Institute, 45 percent of all U.S. pregnancies are unplanned. Since the introduction of the pill, many birth control advances have been new delivery methods for the same hormones that have been used for decades. But about 5.3 million women can't safely take those hormones, often because of previous sicknesses. Millions more simply don't want to be on hormones if they're only occasionally having sex. When a patient asks her doctor for a hormone holiday, says Kelly Culwell, a practicing gynecologist and Evofem's chief medical officer, "we just hand them a bunch of condoms and cross our fingers."

A new form of birth control that doesn't require a doctor to administer, is used only when a woman needs it, and is hormone-free would be a breakthrough. In a clinical trial, Amphora worked about as well as other contraceptive gels. It may also provide protection against chlamydia and gonorrhea.

In the world of new drugs, startup mantras like "Move fast and break things" sound silly.

Unlike other gels, Amphora doesn't contain surfactants, which can cause irritation and make it more likely that a woman will become infected with HIV. And without hormones, Amphora doesn't produce side effects such as weight gain, depression, or nausea. "This could be one of the biggest innovations since the first birth control pill in 1960," says Pelletier.

That would be enough to put Evofem on the path to becoming a billion-dollar company. The current U.S. market for contraceptives is estimated to be about $6.6 billion. About 4.5 million women who are sexually active don't use a contraceptive. Then there's the market for preventing sexually transmitted diseases. "When I was doing my training, we wouldn't put IUDs in anybody," says Andrea Thurman, the director of Conrad Clinical Research Center at Eastern Virginia Medical School. "Now we put them in everybody. It's very possible that 20 years from now, everybody will be using Amphora."

Amphora also puts decision-making power squarely in the hands of women. The gel can be discreetly inserted, via an applicator that looks like a small tampon, up to an hour before sex. A woman's partner can be as involved--or not--as she wishes. "This is for an empowered woman," says Pelletier, emphasizing she doesn't just mean in the U.S. Her plan, if she wins FDA approval, is to distribute Amphora in the developing world on a philanthropic basis.

The drug development regime in the U.S. puts entrepreneurs such as Pelletier in limbo for a terribly long time. The cost of bringing a new drug to market has been estimated at anywhere from $648 million to $2.6 billion, and the timeline can easily stretch to 10 years. Development of Amphora began in the mid-1990s, and the results of its first clinical trial were published in 1999. Pelletier is in what should be the very last stages of this particular form of suffering, and hopes Evofem can bring Amphora to market in 2019. But there is no guarantee it will make the cut.

If and when the FDA does approve Amphora, there is always a chance that women won't flock to it. If that happens, significant modifications to Amphora are pretty much out of the question. In the world of new drugs, startup mantras such as "Iterate" and "Move fast and break things" sound silly. A drug needs to be approved by the FDA, and after that happens, there's not much room for change. Some drugs get just one shot. Amphora is already on its second.

When Pelletier was in first grade, her mother started sending her to school in the kid 
version of a suit: blue trousers and a blue button-up collared shirt with contrasting trim, with her lunch in a small briefcase. Pelletier begged for a lunch pail, like what the other kids had, but her mother told her, "Saundra, school is not about eating."

Her mother's singular mission was to get her daughter out of Caribou, Maine, population 7,736. Pelletier was plenty motivated to leave. Her grandparents had outdoor plumbing, and her family was sometimes on food stamps.

Pelletier went to Husson University in Bangor, and then got a job in sales in the women's health division at G.D. Searle, selling its birth control pills. On Sundays, she would map out the coming week--studying doctors' schedules, composing messages, and choosing treats for the doctors' staffs. "I had this level of discipline that was like, here's the goal, here's how we're going to accomplish it," she recalls. She was awarded a top salesperson distinction, and rose quickly through the ranks. When a colleague told her she would have to stay in her post for three years before she could be promoted, she corrected him: "Maybe you have to stay in your job for three years," she said. "I don't." She got promoted after two years. By the time she was 34, she was a vice president.

But then came the mini midlife crisis. Earlier in her career, she had gone on a safari in Africa with a girlfriend. When the guide asked if there was anything else Pelletier wanted to see, she mentioned health clinics. "I kept remembering all these poor women," she says. "If they're given an opportunity to have access to contraception, they don't have to be poor. It was a very big reality check." She didn't think that her colleagues in women's health necessarily had internalized what women around the world were dealing with. "Even in big pharma, it didn't seem that we understood the gravitas of it--when women can make the right decisions for themselves and their families and how it impacted everyone they touched," says Pelletier. "We wanted to sell product."

Amphora is a hormone-and-surfactant-free contraceptive gel a woman can insert up to an hour before sex. It may also combat some STDs.
CREDIT: Molly Cranna

Pelletier quit her job and became an executive coach. "I had this fantasy that all my clients would be women," she says. "Of course, all my clients were men. Women just don't invest in themselves in that way." She got married. She wrote a book about women's empowerment. She was preparing to spend two years sailing with her husband--and then discovered she was pregnant.

Pelletier was shocked. Doctors had always told her she couldn't get pregnant; now she was 37 and, clearly, they had been wrong. To Pelletier, the pregnancy felt fated. But this was not what her husband had signed up for. "When someone isn't up for that, it's kind of a buzzkill," she says. She told her husband she was having the baby. He could stay or leave, whatever.

Within three years, Pelletier had a toddler, a divorce, and her dream job. In 2009, she was recruited for a role that directly addressed what had been tugging at her all these years: founding CEO of WomanCare Global, a nonprofit that enables sustainable access to contraceptives in the developing world. She couldn't imagine doing anything else--until she got a call in 2013 from an executive of a small health care company called Evomed who was looking for some help marketing and commercializing a new contraceptive gel called Amphora. "My first reaction was, 'I'm flattered. Now please lose my number,'" says Pelletier.

But once she started researching Amphora, she couldn't stop thinking about it. Evomed was working on products in dermatology, pain relief, and menstruation, and had licensed Amphora from Rush University in Chicago. Amphora was in a Phase 3 clinical trial--generally the last hurdle before a drug is submitted for FDA approval.

Pelletier agreed to a three-year consulting arrangement in which she'd write a business plan for the company, raise money, recruit talent, and prepare Evomed for an IPO. In return, Evomed would allow her to keep her position at WomanCare Global. But more important, Pelletier managed to negotiate terms that could help her scale and accelerate her mission: Once Amphora was through the FDA gauntlet, Evomed would sell it in North America and Europe, but it would also give it to WomanCare Global to distribute in the developing world on a philanthropic basis.

Eighteen months in, it became clear to Pelletier that Amphora might never become a blockbuster drug as long as it had to compete for attention within a small conglomerate that had a smattering of unrelated products. She didn't think Evomed's employees had the necessary experience in women's health, or the ability to work at the pace she demanded. "It was everything and the kitchen sink," she says of the operation. "No one was focusing on Amphora as the golden child."

She approached the board with an unexpected proposal: spin Amphora out into its own company and formalize the relationship between the new startup and WomanCare Global as a public-private partnership--with Pelletier running it all.

Six were dead, and among them were the only people who could help her understand the trial on which Amphora's fate seemed to hinge.

Not everyone liked the idea. Pelletier says one of Evomed's bankers and its lawyers objected to her proposed dual role. The way Pelletier saw it, "if I were a man and I said to you that I'd built this amazing nonprofit, and then started working to advance another product that could really help the human condition, you'd say, 'Oh, my god, what a great human being,'" she says. "But because I'm a woman, you suggest I can't manage it all."

Meanwhile, some of her staff at WomanCare Global weren't crazy about the proposal either. Pelletier was equally blunt with them. She pointed out that it was becoming increasingly difficult for nonprofits to find donors. There weren't many private-sector companies willing to partner with nonprofits, which they often derided as being filled with bleeding hearts who can't make good business decisions. "If we can get access to this product that we all believe is game changing and we don't do it, then shame on us," she said. When skeptics accused Pelletier of going back to the dark side, she reminded them: "More money, more mission. Period."

Pelletier became the founder of Evofem Bio­sciences, focusing exclusively on Amphora. She persuaded Evomed's original investors to stay on board, took zero employees with her, found new office space, and hired her own team, which included commercialization pros from major drug companies. "The way I do things is different," says Pelletier. "I need a very disciplined environment."

In December 2014, Pelletier's team was hunkered down in a hotel breakout room in Washington, D.C., preparing to meet with the FDA. It was supposed to be a routine meeting, the kind any company has with the governmental agency before filing for approval. But Pelletier also had something on her mind that she was hoping to get clarity on. She had discovered that a portion of the patients in Amphora's Phase 3 trial were outside the U.S.--in Russia of all places--a move generally frowned upon by the FDA.

More troubling was the fact that no one at Evomed was able to explain why the Russian sites were being used. Drug companies typically outsource their clinical trials to contract research organizations; in this case, it seemed that once Evomed hired its CRO, it didn't pay much attention to the details. "We thought [the head of the CRO] was just a rock star in his field," says Tom Darden, one of the founders of Evomed. "The trial was contracted out with a great deal of confidence in him, and he was managing that process."

Pelletier was planning to teleconference into the meeting with the CRO and the FDA. But as her team was preparing, someone from the CRO arrived with news no one could have anticipated. The CEO of the CRO had decided to fly, piloting his private plane, along with two of his colleagues. It turned out that he'd neglected to de-ice the plane, which led to his crashing into a house and killing everyone on board, and a mother and two children in the home. "It was the most bizarre, shocking thing," says Pelletier. "Everyone at the FDA knew the people at the CRO. They were all crying."

Pelletier was stunned. Six were dead, and among them were the only people who could help her understand the trial on which Amphora's fate seemed to hinge. "That's when we started to be like, 'Oh, my god, this is very stressful and serious,'" she says.

Standing still was not an option. Evofem presented at a conference for investors, and it went well enough that by the spring of 2016, Pelletier had the company on a roadshow to raise $200 million in an IPO. She had written commitments for about half that amount, and was confident she could raise the rest. But during that time, shares in Valeant were crashing over an investigation by the U.S. Securities and Exchange Commission. Prospective investors started getting spooked. Pelletier decided to pull the plug on the IPO, at least for now. Better to try again after FDA approval.

Then, in April 2016, Pelletier finally heard from the FDA. The verdict: It would not accept the Russian data, and therefore it couldn't approve the drug application in its current form. "I was in shock," says Pelletier. "I couldn't even process it. I thought, this cannot be happening."

No matter how much Pelletier tries to bulletproof the current study, Amphora still might not get approved.

Pelletier has adjusted to life in perpetual uncertainty. Evofem's headquarters, on the sixth floor of an office building looking out at the San Diego hills, is filled with indicators that she has no plans to get derailed. In Pelletier's office hangs a quote from writer Rebecca West, which reads in part: "I only know that people call me a feminist whenever I express sentiments that differentiate me from a doormat." It's one of 15 feminist quotes displayed throughout the company's office, although building management made Pelletier remove most of the ones she'd put in the ladies' room on the grounds that they were too provocative for what is technically shared space.

On an August afternoon, executives from both Evofem and WomanCare Global gather inside Pelletier's office for their monthly meeting. The conversation ricochets from startup issues like vendor payments and package design to ones that would sound more at home at an NGO, like the timing of grants from the U.S. Agency for International Development. While the two teams are wildly different operations, their goals are intertwined: If Amphora wins, WomanCare Global could greatly increase its impact, by, say, distributing the product across Africa to sex workers who need contraception that's acceptable to their clients and safe to use multiple times a day.

Throughout the meeting, Pelletier pelts her staff with the same question: "What else? What's left unsaid?"

They all know what's left unsaid: the possibility of failure, that no matter how much Pelletier and her team try to bulletproof the new Phase 3 study, Amphora still might not get approved.

Pelletier hopes Amphora–which is delivered via this tampon-style applicator–will own a sizable part of the $6.6 billion contraceptive market.
CREDIT: Molly Cranna

A little more than a year ago, on the day that Pelletier found out the FDA was rejecting Amphora's application, all she could think about was what she would tell her investors. She gathered her staff in Evofem's boardroom, with its framed pictures of Amelia Earhart and Malala Yousafzai, and told them they had 48 hours to figure this out.

Her team committed to having a new Phase 3 trial design within three months. Pelletier and her CFO agreed to take pay cuts. She would have to lay off six people. Then there were the commercialization experts she'd hired, who now had no product to commercialize. If Amphora could get back on track with the FDA, these employees had the very skills Evofem would need in 12 to 18 months. Pelletier told them she could find jobs for them at Evofem in the interim. "If I do this," she told them, "and you don't really want to be here, I will hunt you down and torture you for the rest of your life." They all stayed.

Pelletier's investors didn't love the fact that they were looking at another trial. But they liked that it took Pelletier "about two minutes" to get back on her feet, says one, and agreed to back her plan. The new goal: FDA approval in 2019.

Now, Pelletier is obsessed with controlling the outcome of the new Phase 3 trial: "I say, every single day, let's control every single thing we know we can control."

She says micromanaging doesn't come naturally to her. Her philosophy is to hire good people and let them do their jobs--except, of course, when she doesn't think they're doing their job well, professionally or personally. During a performance review of one senior employee, she told her she'd get fired if she didn't start dating online. "She was complaining about [not being in a relationship] so much and not doing anything about it. I just couldn't take it any more," says Pelletier. Once the employee put up an online profile, Pelletier got a marketing consultant to rewrite it. The whole episode was creepy--except that it worked, and the employee is now happily married to someone she met online. "Saundra is at the extreme," says Darden. "She gets perfection in execution."

With Amphora beginning its second Phase 3 trial, Pelletier has indulged every control-freak impulse. It could be done with 60 sites, but she's arranged for 115. She's enlisted her head of medical affairs to oversee the trial, even though it's typically tasked to a project-manager-level employee. When the study kicked off in June, Pelletier flew to Atlanta to talk to the people who would be working directly with patients, something CEOs almost never do. She doesn't imagine her new CRO loves all this meddling--but she doesn't care. "They want this study to be over," Pelletier says. "They think we're nuts."

Seeming a little crazy is a small price to pay if it gets her to the only acceptable outcome. Though she easily discusses such uncomfortable topics as her surprise pregnancy, her divorce, and even FDA rejection, her voice cracks when she is asked what would happen if Amphora fails this trial.

If the drug does not get approved--Pelletier swallows--there are options. Evofem might be able to survive by managing drugs developed by other companies. But Evofem would most likely have to sell Amphora, probably to a larger drug company that could market and sell it as a medicine to be used against STDs or bacterial vaginosis. Evofem would get paid royalties, and its investors would get some money back. Pelletier looks like she's going to quietly choke as she explains this.

She would also offer her resignation. She says she did that when the FDA denied Amphora's application, but her investors don't remember it. They say that's possibly because it was the last thing they wanted. They were counting on her to turn this thing around, and if she did offer to resign, they say they dismissed the idea as quickly as they could.

"Honestly, we've done everything right," Pelletier says, with a rare trace of exasperation. "I am here till the bitter end."

How to Survive the FDA

Entrepreneurs in drug development succeed or fail at the hands of the FDA. The long road to approval requires uncommon levels of patience, fortitude--and cash. 

1. Preclinical research
Once a promising substance has been identified, it needs to be tested either in animals or in human cells. After that testing is complete, the developer asks the FDA for permission to begin testing the drug in humans. This is the end of the line for many drug candidates.

2. Phase 1 clinical trial 
The substance is then tested on 20 to 100 healthy people to determine if it's likely to be safe. 

3. Phase 2 clinical trial
The substance is tested for safety and efficacy, often with double-blind studies, so neither the doctors nor the patients know who is getting the drug or the placebo. These can involve several hundred to several thousand patients, and can take anywhere from a few months to a few years.

4. Phase 3 clinical trial
This phase continues testing for safety and efficacy, and can take several years and involve thousands of patients. Once complete, the company or research institution behind the drug can finally apply for FDA approval.

The Result

9.6: Percentage of drugs that enter clinical trials and are eventually approved by the Food and Drug Administration. Source: Amplion

10: The estimated years it takes for a drug to get from research to market. Source: PHRMA

$648 million-$2.6 billion: The estimated cost of bringing a new drug to market.
Sources: Jama Intern Med, Tufts Center for the Study of Drug Development

The Quest for Better Birth Control

Amphora isn't the only game in town when it comes to advancements in contraception.

Caya Diaphragm 
PATH, a global health nonprofit, modernized the diaphragm, which, once popular in the 1940s, had long fallen out of favor among women. The Seattle-based organization's diaphragm is latex-free, easier to insert and remove, and designed to fit about 80 percent of women. It's been on the market since 2015, the year after getting FDA approval. 
 
Sayana Press 
Injectable contraceptives are the most popular form of birth control in some African countries, but using them requires regular access to doctors, a challenge in some regions. This one-piece injectable sold by Merck--which was made available in the U.K. and some E.U. and African countries in 2015--is already loaded, enabling women to administer it themselves. 

Echo-V Gel
With a male birth control pill still a distant dream, Contraline's gel might one day become the closest thing to it. The Charlottesville, Virginia-based startup is working on a nonsurgical, reversible alternative to the vasectomy, of which there are some 500,000 performed every year. Guided by ultrasound, a doctor can inject its gel into the vas deferens, where it solidifies enough to keep sperm from getting out during ejaculation. The early-stage company, which has raised $2.5 million from investors including Founders Fund, is currently doing animal studies--hoping to have a product on the market by 2021.

Correction: An earlier version of this story misstated the infections against which Amphora might be used. They are chlamydia and gonorrhea.