Under FDA’s proposed rule, the labeling would contain two subsections: one on pregnancy and one on lactation. The “Labor and Delivery” subsection would be eliminated because information on labor and delivery is included in the proposed “Pregnancy” subsection.
Current pregnancy labeling uses five categories—A, B, C, D, and X. The categories may mislead healthcare providers (and the women they counsel) to believe that risk increases from category A to B to C to D to X. In fact, that is not the case, because Categories C, D, and X are based not just on risk, but risk weighed against benefit. That means that a drug in categories C or D may pose risks similar to a drug in Category X. In addition, the categories do not always distinguish between risks based on human versus animal data findings or between differences in frequency, severity, and type of fetal developmental toxicities. The proposed rule would remove the categories from the labeling of all drug products.
Both the pregnancy and lactation subsections would have three principal components: a risk summary, clinical considerations, and a data section. These are discussed in more detail below.
Fetal risk summary
The fetal risk summary would begin with a one sentence risk conclusion that characterizes the likelihood that the drug increases the risk of four types of developmental abnormalities: structural anomalies, fetal and infant mortality, impaired physiologic function, alterations to growth. An example of a risk conclusion based on human data is: “Human data do not indicate that Drug X increases the overall risk of structural anomalies.” Many of the risk conclusions in the proposed rule are standardized statements that must be used.
The risk conclusion would state whether it was based on animal or human data. More than one risk conclusion may be needed to characterize the likelihood of risk for different developmental abnormalities, doses, durations of exposure, or gestational ages at exposure.
If there are only animal data, the fetal risk summary would contain only the risk conclusion. However, when there are human data, the risk conclusion would be followed by approximately a paragraph describing the most important data about the effects of the drug on the fetus. To the extent possible, this narrative would include the specific developmental abnormality (e.g., neural tube defects); the incidence, seriousness, reversibility, and correctability of the abnormality; and the effect on the risk of dose, duration of exposure, and gestational timing of exposure.
The Clinical considerations component would address three main topics important when counseling with, and prescribing for, women who are pregnant, lactating, or of childbearing age.
This section would describe known or predicted risks to the fetus from exposure to the drug early in pregnancy before a woman knows she is pregnant, including data on dose, timing, and duration of exposure.
Prescribing decisions for pregnant women
- Risk to the pregnant woman and the fetus from the disease the drug is indicated to treat
- Dosing adjustments during pregnancy
- Adverse reactions unique to pregnancy associated with use of the drug.
- Any interventions that may be needed (e.g., monitoring blood glucose for a drug that causes hyperglycemia in pregnancy)
- Any complications in the neonate associated with drug use, including severity and reversibility, and interventions needed
Drug effects during labor or delivery
For a drug with a recognized use during labor or delivery (whether or not the drug is indicated for that use), include information about the:
- Effect of the drug on the mother; the fetus/neonate
- Duration of labor and delivery
- Possibility of complications, including needed interventions; and the later growth, development, and functional maturation of the child.
The data section would have a more detailed discussion of available data. Human data would appear before animal data. The section would include:
- A description of the types of studies
- Animal species used
- Dose exposure information (animal doses described in terms of human dose equivalents)
- Nature of any identified fetal developmental anomalies and other adverse events
- For animal data, an explanation of what is known about the relationship between drug exposure and mechanism of action in animals versus humans.
Pregnancy exposure registries
Phone number or other information about how to enroll.
General statement about background risk
Statement that all pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure.
If appropriate, include a statement that the use of the drug is compatible with breast-feeding.
- Effects of the drug on milk production
- Whether the drug is present in human milk (and if so, how much)
- The effect of the drug on the breast-fed child
- Ways to minimize exposure to the breast-fed child, such as timing or pumping and discarding milk.
- Potential drug effects in the child and recommendations for monitoring or responding to these effects.
- Dosing adjustment during lactation.
Overview of data on which risk summary and clinical considerations are based.