FDA Issues Guidance for Industry Assessing Reproductive Toxicity

Roxanne Nelson, RN, BSN

May 22, 2019

Cancer is diagnosed relatively rarely in pregnant women. It occurs in about 1 in 1000 pregnancies. Treating cancer in pregnant women is complex. The goal is to optimize cancer treatment while minimizing harm to the fetus. This can be tricky and largely depends on the treatment options, the impact of treatments on pregnancy, and the gestational age of the fetus.

To assist in evaluating reproductive toxicity and the effect on the development of the embryo-fetus, the US Food and Drug Administration (FDA) has announced final guidance for industry on reproductive toxicity testing and labeling recommendations for oncologic drugs.

Although not binding, the new guidance provides recommendations on evaluating toxicity to the growing embryo/fetus for various types of pharmaceuticals and on whether an assessment of reproductive toxicity is warranted for products used by specific patient populations (eg, drugs used only by men or only by postmenopausal women). The guidance also offers recommendations concerning the duration of contraception use after treatment ends, in order to minimize the potential risk to a developing embryo or fetus.

In addition, the guidance clarifies the FDA's current position on when nonclinical studies for reproductive toxicology assessment may not be necessary.

The intended goal of this guidance, according to the FDA, is to facilitate the development of cancer drugs while avoiding the unnecessary use of animals and to provide a more consistent approach to labeling recommendations.

Because cancer rarely occurs during pregnancy, there is a scarcity of research to guide women and their physicians on treatment. Several recent studies assessed the impact of traditional cancer therapies, including chemotherapy, surgery, and radiotherapy, and found that for the most part, it is possible to appropriately treat the mother without terminating the pregnancy. The most common malignancies diagnosed during pregnancy are gynecologic cancers (primarily uterine or cervical, and less frequently, ovarian) and breast cancers, but pregnancy does not have a deleterious effect on a woman's prognosis.

"Guidelines do exist for breast cancer and pregnancy," said Frédéric Amant, MD, PhD, a specialist in gynecologic oncology at Antoni van Leeuwenhoek–Netherlands Cancer Institute in Amsterdam, who chairs the International Network on Cancer, Infertility and Pregnancy of the European Society of Gynecologic Oncology. "This month, we will submit the third guideline in gynecologic cancers in pregnancy," he said.

The field of cancer therapeutics is rapidly expanding, with new classes and types of treatment continually entering the marketplace. The FDA's new guidance, however, does not address the risks of reproductive toxicity from radiopharmaceuticals, cellular and gene therapy products, cancer vaccines, biosimilar or interchangeable products, or generic drugs. It also does not cover safety margins by systemic exposure or dose. For many products, such as small molecules, a safety margin has not been identified.

"Indeed, the new agents are a problem, since there is very little evidence," Amant told Medscape Medical News. "But in the meantime, we are continuing to investigate children and are now preparing a manuscript on the outcomes of 6-year-old children."

He added that this fall, the Society of Human Reproduction and Embryology will be publishing a guideline on preservation of fertility.

Assessing Embryo-Fetal Developmental Toxicity

The FDA notes that when the weight of evidence clearly shows reproductive toxicity for a given drug, there is no need to conduct a dedicated embryo-fetal development (EFD) study. In general, a definitive study is not warranted if a dose-range finding study in which good laboratory practice was ensured demonstrates clear evidence of embryo-fetal lethality or teratogenicity.

For small molecules, EFD studies, when needed, are usually conducted in two species; if a study is positive for teratogenicity or embryo-fetal lethality in one species, it is usually not necessary to conduct one in a second species.

In biotechnology-derived products, a study in one pharmacologically relevant species usually suffices when an EFD study is needed.

Other types of drugs, such as those that are genotoxic, conjugated, or combined, may require different study designs and criteria.

Assessing Fertility and Effects on Prenatal and Postnatal Development

A study of fertility and early embryonic development is generally not needed for drugs that are intended to be used by patients with advanced cancer, because this information should be available from general toxicology studies of the drug's effects on reproductive organs. If the indication is not for advanced disease, there may be a need for stand-alone fertility studies, which are determined on a case-by-case basis.

Similarly, studies are not warranted for prenatal and postnatal development for pharmaceuticals intended to treat advanced cancer. In cases in which the disease is not advanced, such studies may be needed, as determined on a case-by-case basis.

Assessing Risks in Specific Populations

The FDA guidance also addresses the need for assessing risk in specific patient populations and the need for reproductive toxicity studies.

EFD studies are not needed for pharmaceutical agents that are intended to be used by men only, such as treatments for prostate cancer, the authors report. However, the guidelines note that when a drug is not indicated for advanced disease, male fertility studies should be considered, especially if an adequate assessment of fertility that is based on results of general toxicology studies is not available.

Similarly, reproductive toxicity studies are not needed for drugs that are indicated only for postmenopausal women.

When drug indications include children who have entered puberty, EFD assessments should be conducted. Importantly, if the particular therapy is curative or substantially increases survival, the entire battery of reproductive toxicology studies should be considered. There are some some exceptions to this, which are outlined in the guidance.

Recommendations for Contraception

Proposed drug labeling should include recommendations on the duration of contraceptive use after completion of therapy, when it has been determined that there is a risk for reproductive toxicity.

The labeling recommendations are for preventing developmental toxicity, such as malformations and embryo-fetal lethality, not for restoring fertility. Although the recommendations are intended to reduce EFD risk associated with the parent pharmaceutical, the same approach should be used for metabolites of concern, if appropriate. For conjugated pharmaceuticals that contain both a biological and a small-molecule component, both should be considered for labeling.

For men, genotoxic pharmaceuticals can damage DNA in the sperm, which in turn could adversely affect an embryo or fetus. Although there have been no reports of increased malformations in the offspring of men treated with these agents, no comprehensive studies have examined the effects on children who were born within the first year after treatment ended. Additionally, toxicity to the embryo and fetus has been reported in animals when males treated with genotoxic pharmaceuticals were mated with untreated females. Thus, it is recommended that contraceptives be used for 3 months after treatment ends, in order to minimize any associated risk.

For women, genotoxic drugs may directly affect the embryo or fetus or cause DNA damage in the oocytes. The FDA notes that for these drugs, a 6-month contraception labeling recommendation will cover the growth and maturation phase of folliculogenesis and allow for the elimination of most of the damaged follicles and oocytes. Deviations from this labeling recommendation are acceptable when justified, such as for pharmaceuticals that are only aneugenic.

With the use of nongenotoxic drugs in men, there is a hypothetical risk for teratogenicity or embryo-fetal lethality resulting from the transfer of a drug or its metabolites through the seminal fluid to a woman. Studies have not adequately examined effects on children who were born within the first year after treatment completion. Because of the data gaps for small-molecule teratogenic pharmaceuticals, the use of contraceptives is recommended for a period of 5 half-lives, but contraception is not necessary for teratogenic biological products, because they have not been observed to accumulate in the semen and the absorption of such drugs is limited.

Women who receive nongenotoxic drugs known to cause reproductive toxicity should use contraceptives for a period of 5 half-lives after completing therapy. For drugs that do not cause harm to the embryo/fetus, no contraception is necessary.

FDA. Oncology Pharmaceuticals: Reproductive Toxicity Testing and Labeling Recommendations. Published May 2019. Full text

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