FDA recommends collecting ovarian toxicity data in cancer drug trials

The US Food and Drug Administration (FDA) is proposing sponsors collect ovarian toxicity data during cancer drug development. The agency said that cancer drugs may be associated with infertility and certain other morbidities including early onsite menopause and earlier onset cardiovascular disease, and there is a lack of data that may affect patients after they are treated.

On 26 November, FDA published draft guidance for cancer drug sponsors on collecting data on clinical measures and biomarkers for premenopausal adults that may suffer from infertility and morbidities due to the drug. More specifically, the guidance stated that ovarian toxicity should be considered a safety endpoint in trials that include premenopausal adults and should be an integral part of the drug development considerations when the drug is intended for premenopausal patients.

“Loss of ovarian function is a potentially irreversible toxicity associated with systemic anti-cancer agents,” the draft guidance noted. “Ovarian dysfunction may result in infertility and long-term morbidities related to early-onset menopause and estrogen deficiency, including vasomotor symptoms, sexual dysfunction, osteoporosis, and earlier onset of cardiovascular disease.”

The agency said there’s a lack of data on ovarian toxicity from cancer drug trials. It noted that between 2008 and 2019, only 9% of phase 3 (neo)adjuvant breast cancer trials prespecified ovarian function as an endpoint. Furthermore, only 20% of such trials collected pre- and post-intervention ovarian function data, and most just collected data on menstrual status.

“Assessment of ovarian toxicity in cancer trials is essential to ensure that patients and clinicians have information about the possible long-term impacts of cancer treatments on ovarian function and thus facilitate informed decision-making regarding anti-cancer agents,” said FDA.

The guidance recommends sponsors talk to reviewers at the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) early if they plan on enrolling adult premenopausal trial subjects who are likely to have high survival rates. Besides assessing ovarian toxicity in such trials, the guidance recommends sponsors collect gynecological history data, such as menstrual history, pregnancy, and live birth data. It also recommends collecting biomarker data such as serum anti-Mullerian hormone (AMH), serum follicle stimulating hormone (FSH), and serum estradiol (E2) levels, preferably on days 3-5 of the follicular phase of the menstrual cycle.

"At a minimum, sponsors should collect ovarian function measures (clinical, biomarkers, and confounders) at baseline, every 6-12 months while on treatment, at the end of treatment, and at 12-24 months after completion of treatment, and consider additional time points during the study based on the agent and duration of treatment," the guidance recommended. “If there is an identified risk of ovarian toxicity associated with an anti-cancer agent, … the sponsor should assess ovarian toxicity in at least a subset of premenopausal study participants (e.g., N=40) during pre-market trials intended to support a marketing application.”

FDA does make some exceptions for sponsors who can justify not being able to collect ovarian toxicity data in the premarket setting. The agency said in such situations, sponsors should talk to the agency about evaluating ovarian function in the postmarket setting.

The guidance does not apply to pediatric patients, but FDA does list several guidances that do apply to that patient population that cancer drug sponsors should take into consideration.

Stakeholders can comment on the guidance on www.regulations.gov under docket no. FDA-2024-D-4643 until 25 February.

Draft guidance

FDA recommends collecting ovarian toxicity data in cancer drug trials

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