Perspectives

Overview of FDA Guidance for Industry on Assessment of Ovarian Toxicity in Premenopausal Adults During Development for Oncologic Products

Ovarian toxicity is a significant but often overlooked consequence of certain anti-cancer therapies. Ovarian toxicity can cause irreversible loss of ovarian function, leading to infertility and serious long-term health complications, such as early menopause, oestrogen deficiency, vasomotor symptoms, sexual dysfunction, osteoporosis, and cardiovascular disease.

Despite these serious risks, ovarian toxicity data is often underreported in oncology clinical trials. ¹A study found that from 2008 to 2019, only 9% of phase 3 breast cancer trials included ovarian function as an endpoint, and only 20% collected pre- and post-treatment ovarian function data. ² To address this reporting gap, the FDA issued this draft guidance which presents the agency’s current perspective and outlines recommendations for assessing ovarian toxicity.

Scope

This guidance provides recommendations for sponsors on assessing ovarian toxicity ovarian toxicity in cancer clinical trials involving premenopausal adults, particularly those where the life expectancy is long enough for ovarian toxicity to be a relevant concern. The guidance emphasizes the consideration of ovarian toxicity as a safety endpoint in trials for therapies intended for this population. Recommendations related to ovarian function in pediatric cancer patients and nonclinical assessments fall outside the scope of this guidance.

Potential Impact of Guidance on Pharmacovigilance

Informed Consent and Risk awareness: Adverse event (AE) reporting might require documenting patients’ understanding of ovarian toxicity risks, with informed consent clearly highlighting potential risks and long-term follow-up. Respective teams must ensure patients recognize these risks and the importance of reporting ovarian related AEs.

Biomarkers and Long-Term Monitoring in AE Reporting for Ovarian Toxicity: Ovarian toxicity may present through changes in both clinical symptoms and biomarkers (e.g., AMH, FSH, E2), requiring comprehensive data collection and consideration of confounding factors. Pharmacovigilance teams may need to track and report new AE categories, such as menstrual disturbances and long-term effects (e.g., osteoporosis), ensuring extended follow-up periods (6-12 months during treatment, 12-24 months post-treatment). Effective use of biomarkers and long-term monitoring could help in detecting early signs of ovarian toxicity, enabling earlier intervention and precise AE tracking.

Signal Detection, Post-Marketing Surveillance, Labelling, and Risk Warnings for Ovarian Toxicity: Enhanced reporting of ovarian toxicity could strengthen signal detection for anti-cancer drug risks. Pharmacovigilance teams should implement effective methodologies to track ovarian toxicity data, with regular follow-ups (e.g., 6-12 months post-treatment) to monitor long-term effects. Findings could lead to updated drug labelling, including reproductive risk warnings. If pre-market data is insufficient, the FDA may require post-marketing studies and ongoing AE reporting to ensure compliance.

Potential Impact of Guidance on Regulatory Strategy

Early Engagement with FDA for Trial Design: For drugs under PDUFA review, early discussion with the FDA – such as during a Type C or Type D meeting – may be necessary to address ovarian toxicity endpoints. Depending on the drug type, other specialized meetings (e.g., biosimilars, OTC products, etc.) may be required.

FDA Engagement for Post-Marketing Requirements: If ovarian toxicity testing is not feasible during pre-market development, discussion on post-marketing requirements may take place during a Type B, Type C, or Type D meeting. Alternatively, other specialized meetings for Biosimilars, OTC, etc. may be required depending on the drug type.

Update of Drug Labeling: Ovarian toxicity findings may require labeling updates, including Section 5: Warnings and Precautions, to ensure any risks are clearly communicated.

Integration With Expedited Approval Pathways: This additional safety endpoint could influence the expedited approval pathways such as Real-time Oncology Review (RTOR) and Accelerated Approval. For example, ovarian toxicity data may be included in an accelerated approval application to ensure the benefit-risk profile remains favorable.

Recommendations for Sponsors

Sponsors are encouraged to engage with the FDA early when planning trials that may involve premenopausal adults with high survival rates, such as those undergoing adjuvant therapy.

Additionally,Sponsors are encouraged to assess ovarian toxicity in cancer trials involving premenopausal adults using clinical measures and biomarkers, including:

Collect detailed gynaecologic history including menstrual history, prior pregnancies, and live births.
Measure serum anti-Mullerian hormone (AMH), follicle stimulating hormone (FSH), and oestradiol (E2) levels, preferably during days 3-5 of the menstrual cycle’s follicular phase. These biomarkers provide comprehensive information on ovarian function, and Sponsors should standardize laboratory methodologies across sites.
Data collection of confounding factors such as history of hysterectomy, previous pregnancy attempts, and recent use of hormonal contraceptives or any therapies that may impact ovarian function.
Alsoconsider additional methods such as menstrual diaries, investigator-assessed menstrual data, and documentation of reproductive system-related adverse events, including abnormal menstrual bleeding.

At a minimum, sponsors should collect ovarian function data at baseline, every 6-12 months during treatment, at the end of treatment, and at 12-24 months after treatment completion. Additional time points should be considered based on the agent and treatment duration. For therapies with limited data on ovarian toxicity, assessments should continue at additional points, such as 30 days after treatment and beyond the 12-24-month mark.

If a drug has known ovarian toxicity risks based on nonclinical or previous clinical data, sponsors should evaluate ovarian function in at least a subset of premenopausal participants (e.g., N=40) in pre-market trials.

If ovarian toxicity is not assessed in pre-market trials, Sponsors should propose a post-market evaluation plan to FDA. This plan should include:

Enrollment of at least 40 premenopausal adults, with follow-up data collection.
Characterization of ovarian toxicity incidence and severity at least 12-months post-treatment.
Follow-up assessments, including AMH, FSH, and E2 measurements, at 6-month intervals and at 12 months post-treatment.

Conclusion

Assessing ovarian toxicity in clinical trials is essential to ensure patients and healthcare providers are well-informed about the potential long-term impacts on ovarian function. This enables better decision-making regarding cancer therapies and reproductive health. The aforementioned FDA guidance document aims to enhance safety monitoring and provide critical information on the ovarian effects of oncologic product development, focusing on comprehensive assessments for premenopausal adults.

Sponsors can work with an experienced regulatory and pharmacovigilance team to integrate ovarian toxicity endpoints into trial designs from early planning stages and engage with the FDA throughout the submission lifecycle. The post-marketing assessments, including potential labeling updates, should be considered to ensure continued safety monitoring and transparent communication on reproductive risks.

This article was written by Regulatory Affairs Associate Aaron Pyle and Principal Medical Reviewer Chandan Raj at MMS.

References

Cui W, Francis PA, Loi S, Hickey M, Stern C, Na L, et al. Assessment of Ovarian Function in Phase 3 (Neo)adjuvant Breast Cancer Clinical Trials: A Systematic Evaluation. J Natl Cancer Inst. 2021;113(12):1770-1778.
Nalubola, P. Assessment of Ovarian Toxicity in Premenopausal Adults During Drug Development for Oncologic Products. U.S. Food and Drug Administration website. 2024.