The effort to get FDA approval for drugs currently used off-label in “gender-affirming care”

A non-profit called Research Institute for Gender Therapeutics (RIGT) was formed with the express purpose of securing FDA approval for drugs currently used off-label in so-called gender-affirming care. According to the RIGT website, they are actively pursuing FDA approval of testosterone as a masculinizing agent and estradiol as a feminizing agent. Madeline Deutsch, director of the University of California, San Francisco’s Gender Affirming Health Program, told Axios that FDA approval would not change how doctors prescribe these drugs, rather it would “bring additional legitimacy to the treatment and could make insurance companies more willing to cover the drugs”. The company has also stated that they plan to eventually seek FDA approval for puberty blockers.

According to the above article in StatNews and a RIGT press release, RIGT submitted a voluntary request for feedback from the FDA on a proposed clinical study to support an approval application for estradiol. In its response, the FDA:

• recommended that RIGT include minors aged 13-17 in its study population instead of limiting enrollment to adults.
• recommended that RIGT forego a placebo control in its study.
• agreed with RIGT that the effect on secondary sex characteristics was an appropriate endpoint for the study.

This feedback suggests the FDA is open to deviating from its rigorous drug approval standards for drugs used in so-called gender-affirming care.

What is the status of RIGT’s effort to get FDA approval for estradiol?

The FDA feedback came in response to a drug development plan, which RIGT voluntarily submitted to receive advice from the FDA on how to design a clinical study to support FDA approval of the drug. It is important to note that the FDA’s feedback is nonbinding.

Before RIGT can receive approval, it will still need, at a minimum, to receive FDA approval of an Investigational New Drug (IND) application, conduct the IND study (with approval from an Institutional Review Board to ensure the protection of human subjects), and receive FDA approval of a New Drug Application (NDA). 

RIGT estimates they will begin their clinical study in 2025. Under the most favourable conditions, it is very unlikely they could receive FDA approval for estradiol before 2027.

Why should I be concerned?

Although the FDA’s feedback is nonbinding and no drug application (NDA) or even request to initiate a clinical investigation (IND) has been submitted to the FDA, the FDA’s feedback is still concerning because it shows the FDA is willing to allow looser standards of approval for “gender medicine.”

The FDA usually expects drug sponsors to conduct studies of their drugs in adults before studying them in children. However, the FDA recommended that RIGT enrol adults and adolescents in the same study. This could mean that the FDA believes safety and clinical benefits have been sufficiently established in adults to allow a clinical study in children. This is not true. Multiple systematic reviews of the use of hormones to treat gender dysphoria have found existing evidence to be poor or very poor.

Placebo-controlled trials provide the best evidence of effectiveness. However, the FDA recommended that RIGT not include a placebo control group, meaning the FDA could accept a study with a no-treatment control group or a historical control. This raises at least two concerns:

• First, studies that do not contain a placebo control group produce less reliable data because they do not as effectively eliminate bias. This means the FDA may be positioning RIGT—or some other sponsor—to receive FDA approval based on flawed data. FDA approval may make insurance coverage more likely and may encourage more people to pursue hormone treatment for gender-related distress, instead of other, less harmful interventions (like exploratory therapy).
• Second, the decision to allow a study without a placebo may signal that the FDA believes that data supporting the use of hormones to treat gender distress is strong, and withholding treatment from the placebo group would be unethical. Neither of these things is true but if the FDA believes them, the FDA may be predisposed to approving powerful drugs that have not been shown to be effective.

The FDA has advised RIGT to design their study to show that estradiol affects secondary sex characteristics, such as breast development and other superficial, cosmetic changes. But RIGT is seeking to support approval of their drug as a treatment for gender incongruence. It is much easier to demonstrate an effect on an easily measured cosmetic trait than on psychological health. As an analogy, imagine if a manufacturer of breast implants claimed its product could treat body dysmorphia based on a study that showed only that breast implants reliably increase breast size. The FDA would never allow that, yet they appear to be open to allowing mental health-related claims based on a study designed only to show an effect on a cosmetic endpoint. Again, the FDA may be clearing a pathway towards approval based on data that does not establish a clinical benefit, potentially exposing more vulnerable people with mental disorders to potent ineffective drugs.

What should be done?

The public must be made aware that the FDA seems to be lowering the bar to create an approval pathway for powerful drugs intended for lifelong use with multiple serious side effects and unproven effectiveness. The STATnews piece does not question the FDA’s actions. It is important that additional pieces appear in the press scrutinizing the FDA’s feedback, showing how it deviates from usual standards for drug approval, and exposing the potential consequences of FDA approval based on sub-standard science.

The FDA should also be held accountable through the oversight process. While the FDA will not answer questions about RIGT’s potential application unless and until RIGT receives NDA approval, the FDA can be forced to answer general questions about its approval standards and whether there is any reason why gender medicine should be subject to lower standards. In addition, the FDA should be put on notice that any approval of gender medicine based on relaxed standards will provoke blowback. FDA officials should be asked to testify at a Congressional hearing about the agency’s approach to drugs used in gender medicine, including (1) whether the FDA will relax its traditional requirement of two adequate and well-controlled studies to support approval; (2) whether the FDA will accept surrogate endpoints for such studies, including purely cosmetic endpoints; (3) what the FDA is doing about direct and indirect promotions of the off-label use of puberty blockers and cross-sex hormones; and (4) whether the FDA will consider commissioning systematic reviews of these drugs and taking other actions requested by the Citizen Petition filed with the FDA on September 1st.

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