Nevertheless, they persisted

March 9, 2023
How drugmakers are fighting to keep reproductive health drugs available, safe and legal
It’s a table at which most companies don’t want to sit.

In modern day corporate America, companies are quick to belly up to certain causes — flying blue and yellow Ukrainian flags, blacking out social media in solidarity of racial justice, or switching to rainbow logos for Pride month. And yet, when it comes to reproductive rights, many companies don’t seem to have much of an appetite for activism.

When the Supreme Court of the United States overturned Roe v. Wade last June, companies’ long-standing silence got awkward. The pharma industry responded much the same way most businesses did — a handful of companies spoke up, with many somewhat skirting the issue by mentioning their own health care policies.

For most of the pharma industry, abortion is not a kitchen-table issue. Yet, for drugmakers focused on reproductive health, balancing drug manufacturing and reproductive justice is a familiar exercise. Even before the fall of Roe, drugmakers producing oral contraceptives, emergency contraceptives and medical abortion drugs have lived in a unique world of red tape, ideological opposition, stigma, misinformation and legal unease.

Samantha Miller, co-founder and co-chief executive officer at Cadence OTC, spent more than two decades working in the more traditional biopharma industry but says her foray into the reproductive health space was the first time she encountered this type of environment. “It definitely stretches companies beyond traditional activities into the political and advocacy realm,” says Miller.

Now, the maelstrom effect of Dobbs v. Jackson has sucked in more than just access to abortion services. The decision has created confusion and chaos surrounding women’s constitutional right to reproductive health. Currently, a Texas lawsuit seeking to overturn the Food and Drug Administration’s approval of mifepristone, a medical abortion drug, is capturing media headlines. A lawsuit challenging state medical abortion bans, filed by a mifepristone manufacturer, is also underway in West Virginia. The outcomes of both lawsuits could have trickle-down effects that leak even further into the reproductive health drug space.

The need to secure access to all reproductive health drugs has become imperative — even for medications backed by decades of safety data. Against this backdrop of urgency, a handful of determined drugmakers are continuing to innovate ways to get safe, effective reproductive health drugs into the hands of people who need them.

Disunited states

Returning the power to regulate abortion to individual states has resulted in diverging reproductive health regulations — and drugmakers, as well as the FDA, are finding themselves caught in the middle.

According to attorney Skye Perryman, president and chief executive officer for Democracy Forward, a legal advocacy organization formed in the wake of the 2016 presidential election, while the effect of the Dobbs decision on women’s rights is “incredibly concerning,” it has also “emboldened a broad range of conduct that continues to be both harmful and unlawful, even in the wake of Dobbs.”

Much of this conduct is playing out in the courts. Bearing the brunt of the legal fallout is the medical abortion drug, mifepristone. There are currently only two small drugmakers manufacturing mifepristone for the U.S. market: New York-based Danco Laboratories, which won approval for the branded drug, Mifeprex, in 2000, and Las Vegas-based GenBioPro, which got the nod for the generic tablets in 2019.

The FDA-backed protocol for medical abortion — which now accounts for more than half of U.S. abortions — is to take two drugs in combination, mifepristone and misoprostol. While misoprostol can be used alone for medical abortions (the regime is supported by the World Health Organization and used internationally), in the U.S., misoprostol is only approved as a standalone treatment for gastric ulcers. Thus, removing mifepristone from the equation would complicate medical abortion in the U.S., forcing health care providers to use misoprostol off-label.

Back in January, GenBioPro, the generic drugmaker that controls the largest share of the U.S. mifepristone market, decided to go on the offensive. The company, which was launched in 2012 with the mission to bring generic mifepristone to market, filed a potentially landmark lawsuit alleging that the heavy restrictions that have been in place in West Virginia, combined with the criminal abortion ban enacted post-Roe, have halted access to mifepristone and the company’s ability to do business in the state.

GenBioPro sells only two products — generic mifepristone and misoprostol. Sales from the two medical abortion drugs are the company’s sole source of revenue.

“In nine states with state abortion bans or no abortion clinics in operation, we have seen a 100% decline in sales,” says a GenBioPro spokesperson.

In addition to the business case, the suit appeals to the company’s founding principle of access advocacy.

“We are taking on this litigation because it is central to our mission of protecting access to reproductive health care. Since we brought our first product to market, we have been clear that protecting access to reproductive health care is a key priority of ours,” says the GenBioPro spokesperson.

The West Virginia lawsuit is not the company’s first dive into legal waters. Back in 2020, the drugmaker filed a lawsuit in Mississippi challenging statewide abortion restrictions, but voluntarily dropped the suit following the state’s success in persuading the Supreme Court to overturn Roe v. Wade. At the time, GenBioPro indicated it would revive the suit elsewhere — a promise the drugmaker appears to have delivered on in West Virginia.

“West Virginia is maintaining a series of laws and regulations that are in conflict with the federal regulatory structure,” says Perryman, who is part of the robust legal team representing GenBioPro. “We know the harmful impact that has on mifepristone access and it’s unlawful. But you can imagine the broader implications of this as well.”

As the mifepristone legal battles unfold, exactly how broadly their implications reach within the reproductive health drug space will become more apparent.

Standing with safety

With the ink barely dry on Dobbs v. Jackson, a Trump-appointed federal judge in Texas holds the pen on what will likely be the next high profile ruling on abortion. Last November, four anti-abortion medical associations represented by Alliance Defending Freedom, a conservative Christian legal group, filed a lawsuit challenging the FDA’s approval of mifepristone. The Alliance for Hippocratic Medicine v. FDA suit contends that the agency approved the drug without proof of safety under the labeled use conditions and then continued to disregard its safety issues.

In mid-January, Danco Labs, a little-known company that, by design tends to fly under the radar, filed a motion to intervene, joining the defense in the ongoing lawsuit. In a press release, Danco, whose sole marketed product is Mifeprex, noted its concerns about a judge blocking the availability of Mifeprex nationwide as well as a weightier issue — the “direct challenge to the FDA approval process for all pharmaceutical products.”

The case has incited a flurry of legal speculation — as well as panicked headlines — regarding the broader consequences of challenging FDA approvals. First mifepristone, then what?

The FDA, for its part, is standing by mifepristone’s robust, evidence-based approval — a review process that took the agency close to five years to complete. In the event that court proceedings force the agency to start the congressionally mandated process to re-review the drug, 23 years of safety and efficacy data should ultimately prevail.

In fact, some argue that the FDA regulation of mifepristone’s safety risks is too strict — and that it’s hampering access to the drug. Mifeprex and generic mifepristone are available under the FDA’s rare risk evaluation and mitigation strategy (REMS). Established in 2007, REMS programs are put in place for certain medications with serious safety concerns to help ensure the benefits outweigh the risks. Out of more than 20,000 FDA-approved drug products, there are only 61 individual and shared REMS programs.

Early in the pandemic, the FDA relaxed the in-person dispensing requirement in mifepristone’s REMS, allowing the drugs to be dispensed by mail. In January 2021, the Supreme Court granted a Trump Administration request to reinstate the in-person requirements. Later that year, the FDA began a review of the REMS program, asking both drugmakers to submit updated prescribing information and REMS materials. The updates were approved by the FDA and went into effect on January 3, 2023.

The updates allow for mifepristone to be dispensed by mail and retail pharmacies, however the pharmacies must be specially certified and execute the required ‘pharmacy agreement form’ with either Danco Labs or GenBioPro.

While this decision was heralded as a win for abortion drug access, some, including a dozen Democratic-controlled states, think it doesn’t go far enough. The states are now also suing the FDA, seeking that the agency remove the mifepristone REMS entirely. The suit, filed in a federal district court in Washington state in late February, points to decades of safety data, questioning why mifepristone is put in the same category as dangerous and addictive opioids like fentanyl.

The states’ suit does not mention the Texas case specifically, however the states are asking that the court declare that “mifepristone is safe and effective” and that the FDA’s approval of mifepristone is “lawful and valid.” The plaintiffs are also asking the court to prevent the FDA from “taking action to remove mifepristone from the market or reduce its availability.”

The 1938 Federal Food, Drug and Cosmetic Act granted FDA sole authority to regulate drugs, so many FDA law scholars assert that there is no judicial ‘magic wand’ that can wipe mifepristone — or any approved drug — from the market. The reverse should also hold true; a judge can’t force the agency to keep a drug on the market.

Ultimately, mifepristone’s market fate comes down to safety — a case that both Danco Labs and GenBioPro are confident they have the data to make.

Born into controversy

A lesser-discussed concern lurking in the depths of Dobbs and mifepristone litigation is that states could plunge further into the reproductive health space and seek out ways to restrict access to birth control.

The right to contraceptives was first recognized by the Supreme Court in 1965, and since then, attempts to codify that right into law — such as the Right to Contraception Act — have failed along party lines.

But in the oral contraceptives space, access barriers are nothing new and were initially so pronounced that drugmakers had little interest in bringing a birth control pill to market.

‘The pill’ was born into religious opposition and an inhospitable legislative environment. It wasn’t until 1957, when drugmaker G.D. Searle won FDA approval for a drug that combined progesterone and estrogen — as a treatment for menstrual disorders — that the business case was realized. By 1959, half a million American women were being prescribed the drug, branded Enovid, presumably not for menstrual disorders.

Three years later, the FDA approved Enovid as the world’s first commercially produced oral contraceptive — but the drug regulator’s decision clashed with existing state laws. More than half of U.S. states had anti-birth control laws on the books, restricting contraceptives. One of the strictest, Connecticut’s Barnum Act, banned information, advertisement or sale of any type of birth control.

It took a deliberate act of civil disobedience by the executive director of the Planned Parenthood League of Connecticut, Estelle Griswold, and a Supreme Court ruling (Griswold v. Connecticut, 1965) to legalize birth control for married couples. A second Supreme Court ruling (Eisenstadt v. Baird, 1972) was necessary to extend that right to unmarried people.

Despite the state-level controversy over birth control, the market for oral contraceptives flourished. By 1970, seven different pharma companies had received FDA approvals for birth control pills and 13 major drug companies were actively pursuing birth control research and development. By the early 1980s, 10.7 million American women were taking oral contraceptives.

Planning for the future

While no state has sought an outright ban of oral contraceptives in modern times, state policies can both enable and restrict access to contraceptive care.

In 2017, Iowa opted to leave the federal Medicaid family planning program and establish its own state-run program that would exclude any clinics associated with abortion from funding. Unfortunately, many women were relying on these clinics for access to oral contraceptives. A Guttmacher Institute study found that the Iowa policy changes, driven by anti-abortion ideology, led to serious disruptions in access to affordable contraceptives.

The federal Medicaid statute does classify family planning as mandatory, and overall this has made oral contraceptives more available to those who qualify. However, there are still many Americans who struggle with access.

“The bigger issue is people who are uninsured,” says Nap Hosang, co-founder, co-chief executive officer and chief medical officer for Cadence OTC. “It’s the people who are in between — not low income enough to be on Medicaid but do not have access to insurance.”

A 2022 Kaiser Family Foundation Women’s Health survey reported that one in five uninsured females of reproductive age had to stop using a contraceptive method because they couldn’t afford it.

A disturbing statistic lends credence to the persistence of access barriers: Despite a plethora of safe and legal contraceptive options, unintended pregnancies in the U.S. are hovering at around 50%. The desire to solve this issue prompted a group of reproductive health experts and pharma leaders to come together in 2016 and take action, launching Cadence OTC.

“Unintended pregnancy was public health issue that needed major attention in the United States,” says Hosang. “We needed to do something about accessibility of the birth control pill.”

Formed with the mission to bring oral contraceptives over the counter, Cadence OTC is a small California-based, public benefit company (PBC) — a unique legal designation in the pharma space. PBCs essentially have a double bottom line in their company charters, meaning the company must make business decisions geared towards generating both profits and positive social impact. Cadence has spent the last seven years working to deliver on this dual promise.

Freeing the pill

In order to initiate the first-in-class Rx-to-OTC switch, Cadence had to first acquire the rights to a branded drug.

“There are only a small number of NDA [New Drug Application] owners in the world for regular combined oral contraceptives,” explains Miller. “And the drug needed to be the mainstream dosage and we wanted it to be the progestin molecules that are considered the safest in the class, which is levonorgestrel.” Miller’s first mission at Cadence was to find this NDA needle in the predominantly generic drug haystack.

In 2018, Cadence bought the rights to two estrogen-progesterone combo oral contraceptives, Lo/Ovral and Alesse, from Pfizer. Pfizer had picked up the pair as part of its 2009 takeover of Wyeth-Ayerst Laboratories.

NDAs in hand, Cadence set out on the long road towards OTC approval for the drug it has branded as Zena. The company is currently focused on consumer label pivotal studies.

“Label development involves taking the physician package insert and communicating all of that information in a way that consumers can understand — and not only the average consumer, but adolescent consumers and low literacy consumers,” says Miller. “It’s a long, extensive process because you’re constantly developing the label, testing it with consumers, changing it and testing it again.”

Cadence has been collaborating closely with the FDA to develop a technology-assisted label under the agency’s new additional condition of nonprescription use (ACNU) program. The proposed ACNU rule, released by the agency in June 2022, makes it clear that the FDA is willing to accept new ways for consumers to appropriately use drug products without the supervision of a health care practitioner.

Because certain groups of women — such as smokers over age 35 or those with uncontrolled high blood pressure — have an increased risk of serious complications from oral contraceptives, an OTC label must enable consumers to self-select for such conditions. Cadence’s label uses a QR code to get to a web-based health questionnaire that asks consumers health-related questions to determine whether the product is right for them or whether they should speak with a physician first.

Once the label is developed and tested, Cadence can move on to the final step, the actual use trial, during which the company will test Zena’s use in a real-world setting. The pot of gold at the end of the actual use trial, should the drug get approved for the switch, is a three-year period of exclusivity.

Cadence started the regulatory process long before the fall of Roe, but the current climate has added new meaning to the mission.

“Cadence is under more pressure to move quickly and we are receiving more support as well,” says Miller. “So we are more determined than ever despite the many impediments on the path.”  

Pushing oral contraceptives over the counter has the endorsement of major medical associations, policymakers, and high-profile advocacy groups. The country may have an answer soon too — while Cadence has not yet submitted its application to the FDA, Paris-based HRA Pharma filed to switch its progestin-only birth control pill with the agency last summer.

If history is any indicator, the mission to bring a reproductive health drug over pharmacy counters is not for the faint of heart. The sector’s only example is the emergency contraceptive drug, Plan B, which took ten years to go from prescription to OTC. Susan Wood, who resigned her position as head of the FDA’s Office of Women’s Health because of the Plan B regulatory delays, later referred to the unfoldings as a “tortuous, and indeed politicized, process of approving a safe and effective, but time-sensitive, contraceptive product for over-the-counter sale.”

Undeterred by cautionary anecdotes, Cadence — per the company’s mission — remains focused on knocking down obstacles between women and reproductive health options.

“Part of being part of this movement involves recognizing that we need to pay attention to not only the social consequences of lack of access, but also to the rights of all people seeking contraception,”  says Hosang.

Joined in dissent

The acute pain of the Dobbs v. Jackson decision has slowly given way to chronic aches throughout the reproductive health drug space. Drugmakers looking to bring new drugs to market — or keep old drugs on the market — face a disparate landscape of laws and beliefs.

While roadblocks are part and parcel for the reproductive health space, drugmakers continue to find ways to keep drugs accessible. And they have decades of safety data — plus the collective voices of millions of advocates — fighting on their side.

“Those of us in the field need to just stay tuned and keep pushing because none of the gains we have had in the past 50-100 years have come easily. For us to make substantial gains going forward, those who are committed need to just keep pressing ahead,” says Hosang.

About the Author

Karen P. Langhauser | Chief Content Director, Pharma Manufacturing

Karen currently serves as Pharma Manufacturing's chief content director.

Now having dedicated her entire career to b2b journalism, Karen got her start writing for Food Manufacturing magazine. She made the decision to trade food for drugs in 2013, when she joined Putman Media as the digital content manager for Pharma Manufacturing, later taking the helm on the brand in 2016.

As an award-winning journalist with 20+ years experience writing in the manufacturing space, Karen passionately believes that b2b content does not have to suck. As the content director, her ongoing mission has been to keep Pharma Manufacturing's editorial look, tone and content fresh and accessible.

Karen graduated with honors from Bucknell University, where she majored in English and played Division 1 softball for the Bison. Happily living in NJ's famed Asbury Park, Karen is a retired Garden State Rollergirl, known to the roller derby community as the 'Predator-in-Chief.'