Evaluating the impact of FDA’s pregnancy and lactation labeling rule


Since 1979, obstetric and other health care providers who treat pregnant or potentially pregnant and breastfeeding women have relied heavily on the Food and Drug Administration’s pregnancy labeling categories for pharmaceuticals – the familiar A, B, C, D, X. However, as early as 1997, a public hearing was held that challenged the value of these labels as typically used in clinical practice by both providers and patients.

Now, 17 years later, in December 2014, the FDA has released the “Pregnancy and Lactation Labeling Rule” (also known as PLLR or final rule). In brief, the revised label will require that:

• Contact information be prominently listed for a pregnancy exposure registry for the drug, when one is available.

• Narrative sections be presented that include a risk summary, clinical considerations, and the supporting data.

Dr. Christina D. Chambers

Dr. Christina D. Chambers

• A lactation subsection be included that provides information about using the drug while breastfeeding, such as the amount of drug in breast milk and potential effects on the breastfed infant.

• A subsection on females and males of reproductive potential be included, when necessary, with information about the need for pregnancy testing, contraception recommendations, and information about infertility as it relates to the drug.

The labeling changes go into effect on June 30, 2015. Prescription drugs and biologic products submitted for FDA review after that date will use the new format immediately, while labeling for prescription drugs approved on or after June 30, 2001, will be phased in gradually.

Why are these changes needed, and what impact will they likely have for clinical practice?

First a bit of history – the pregnancy label A, B, C, D, X categories were initially introduced in the 1970s, following the recognition that thalidomide was a human teratogen. The intention was to help the clinician deal in a more standardized way with the increasing amount of experimental animal data and human reports generated for drugs that might be used by women of reproductive potential.

However, the letter categories, and their accompanying standard text statements, were frequently misinterpreted in oversimplistic and inaccurate ways (Birth Defects Res. Part A 2007,79:627-30). Clinicians and patients often believe that risk increases as you move across the letter categories; for example, that a category C drug is worse than a category B drug for a given patient.

Clinicians and patients also commonly think that drugs in the same category have the same level of risk, or that there is a similar quantity and quality of information to support that risk category. Frequently cited examples of misinterpretation include those drugs assigned a category X, for example, label text indicating that the drug is “contraindicated in women who are or may become pregnant.” In reality, in some cases, the X category has been applied to drugs with known human teratogenic potential (such as isotretinoin or thalidomide). However, in other cases, the X has been assigned to drugs for which there were no or very limited human data indicating risk (such as ribavirin or leflunomide) or for which the treatment for the underlying condition would not be necessary or advisable in pregnancy (such as statins or some weight loss drugs).

There is no differentiation made in the category X label for varying risks specifically related to dose and timing of exposure in gestation. In each of these situations where there are no clear-cut human data, inadvertent exposure to the drug in an unplanned pregnancy can easily lead to the misunderstanding that the drug is known to cause birth defects in humans.

The immediate impact of the PLLR label revision will be to require narrative sections that describe the actual data, provide a summary of risks, and also present clinical considerations that may include the risk of undertreatment or no treatment with the drug. The new format is intended to provide the clinician (and the patient) with more comprehensive information on which to base decisions.

The downside of the label revision is that clinicians will have to learn to interpret more comprehensive information and deal with the unknowns, which are many.

The other major impact of the label revision will be to highlight the clear lack of sufficient human data for most drugs currently marketed in the United States. A recent review of drugs (both prescription and over the counter) approved by the FDA between 2000 and 2010 found that 73.3% had no human data available that was relevant to pregnancy safety (Am. J. Med. Genet. C. Semin. Med. Genet. 157C:175-82).

In the short term, the learning curve for label writers and the end users of such labels will be steep. However, clinicians and patients can contribute to the compilation of data for most drugs by more proactively engaging in pregnancy and lactation safety studies. Information about the existence of any pregnancy registries in drug labeling has been recommended in the past, but will now be required. Acting on that information by enrolling patients in these studies can ensure that labels can more quickly be populated with evidence-based data that can better inform patient care.

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