The push to get estrogen FDA-approved for gender-affirming care

Hormone replacement therapies have long been approved by the Food and Drug Administration for use by cisgender patients, such as women who take estrogen when going through menopause. Now, for the first time, a nonprofit group is pursuing research with the goal of FDA approval for the use of estrogen as a gender-affirming treatment for transgender and gender-diverse patients.

The group, the Research Institute for Gender Therapeutics (RIGT), was founded earlier this year with the mission of obtaining approval for gender-affirming hormones, which are currently prescribed to patients off-label without an explicit approval for trans health care. RIGT submitted a development plan to the FDA for a Phase 3 clinical trial focused on estradiol — the most common form of estrogen for hormone treatments — and received the agency’s written feedback on Nov. 17 in lieu of a live pre-investigational new drug meeting. STAT reviewed both RIGT’s proposal and the FDA’s feedback.

In response to the group’s plan, the FDA “positively surprised” the group by advising them not to do a placebo-controlled trial, said Brad Sippy, RIGT’s founding director and president. The FDA also suggested widening the study’s population to include adolescents as young as 13 years old. The feedback comes at a time when many states are banning hormone treatment and puberty blockers for youth.

“[The FDA’s] feedback validates that this [gender incongruence] is a treatable condition and validates the existence of that population, and really gives us a pretty clear path to a federal approval for gender-affirming care,” said Sippy.

The FDA “generally cannot confirm or deny the existence of a pending product application or discuss the status of a pending application,” April Grant, a press officer for the agency, said in an email.

While the agency is limited in what it can disclose, a spokesperson noted that, “FDA’s advice regarding how to translate a sponsor’s proposal into more specific terms should not be interpreted as FDA necessarily proposing or recommending a different approach.”

RIGT’s estradiol research program is its first, but the group has plans to pursue FDA approval for testosterone in gender-affirming care, too. After receiving the FDA’s feedback to include adolescents in the study, it’s also hoping to later pursue approval for puberty blockers.

“It’s critically important to secure FDA approval for gender-affirming hormones and pubertal suppressants,” said Alex Keuroghlian, an associate professor of psychiatry at Harvard Medical School and the director of education and training programs at The Fenway Institute, which focuses on LGBTQ+ health research and policy. Keuroghlian is not associated with RIGT, but sees FDA approval as an important step in making sure gender-affirming care is accessible to those who need it.

RIGT’s original proposal was a double-blind placebo-controlled study, Sippy said. But the FDA noted in its feedback that other study designs may be more appropriate. The agency didn’t provide explicit reasoning for this, but some experts on gender-affirming care have noted that it can be both unethical and impractical to attempt randomized controlled trials with gender-affirming hormones. Not only is there a robust body of evidence that the treatment can prevent serious harm to patients, particularly with respect to mental health, but the physical effects of the treatment make it difficult to obscure whether somebody is receiving it or not. People on estrogen often experience breast development and less hair growth, among other physical changes.

The study population that RIGT initially put forward was limited to adults and adolescents of reproductive age who had not taken puberty blockers, as the organization wanted to stick as tightly as possible to the typical industry drug development course, which focuses first on adult populations. But the FDA encouraged the group to include adolescents as young as age 13, including those who have taken puberty blockers.

“They practically wrote the inclusion section themselves,” Sippy noted. “Not only do we feel that they’re in agreement, but they’re actually stretching the boundaries in ways that we wouldn’t have advocated ourselves.”

FDA feedback also supported the group’s use of “gender incongruence” as the treated condition, and secondary sexual characteristics — those physical changes like early breast development that come with puberty or through hormone treatment — as the primary endpoint of the proposed study. This signals support for the categorization of transgender and gender-diverse identities as related to sexual health rather than mental health, as the Diagnostic and Statistical Manual of Mental Disorders term “gender dysphoria” indicates.

“We are pushing, and it seems as though the agency agrees, that this is a sexual health condition,” said Nicole LaRocque, a founder and chief operating officer at RIGT. This guidance follows the latest edition of the World Health Organization’s International Classification of Diseases, in which the condition of gender incongruence was categorized under sexual health.

Before starting the study, the group must continue to fundraise — it’ll have to purchase estradiol for the study and potentially partner with established researchers to conduct it. It’ll also need to settle on the type of estrogen treatment it will use. With a placebo trial, pills would have been easier, but with the new directive, injectables are more popular and potentially more accessible in the market.

The group will also need to create the new study design, which will need official FDA approval for safety, as well as the approval of an institutional review board for safety and ethical considerations. With the work ahead, Sippy and LaRocque anticipate that the study will begin in 2025.

Those who argue against gender-affirming care often cite the lack of FDA approval for hormone treatments in their arguments. But even if hormone therapies do eventually receive approval for trans patients, Keuroghlian doesn’t think that will put a stop to the opposition. “Because I don’t think that movement is actually based on science or evidence or regulatory policy,” they said. In the similarly political battle over abortion as medical care, anti-abortion groups have sued the FDA over its decades-old approval of mifepristone — a case that may go to the Supreme Court after plaintiffs won an appeals court ruling limiting the use of the medication.

Sippy and LaRocque, who both have close family members who are trans or nonbinary, want to prevent any further limits on gender-affirming care by pursuing FDA approval.

“I’m the parent of a trans kid, and I’m going through the process now of researching what’s the best medical care,” LaRocque said. “And the care is out there.”

This article was updated to note that STAT reviewed RIGT’s proposal and the FDA’s feedback, and clarified the feedback on study design.  The article was later updated to include further comment from the FDA.