FDA’s Pregnancy Reg Could Be Template For Other Product Risk Descriptions

FDA's proposed regulation for the new format of the pregnancy section of labeling appears to offer firms a useful template for how to structure other risk disclosures about products.

Although in development for over a decade, the document is being released just as FDA is fleshing out how to use the new safety powers it acquired last year as part of the legislation that renewed the drug user fee program.

Much of the early attention has been rightly focused on how FDA is requesting distribution limits and post-marketing studies to better control and understand the potential risks of new products. But another part of FDA's expanded authorities includes being able to require quick labeling changes, and through that, the ability to alter marketing messages.

For an industry that has at times been concerned that FDA would rush to post insufficiently vetted risk information, the proposed pregnancy rule should offer reassurance that FDA wants to place drug risk in context.

The ¹ proposed rule would require companies to separate labeling into three categories for pregnancy and lactation - fetal risk summary, clinical considerations and data (² (Also see "FDA “Xes” Letter Categories For Pregnancy Labels; Data Collection Drives Reg" - Pink Sheet, 2 Jun, 2008.) p. 3). The additional content would increase the overall length of labeling by a weighted average of 3,200 characters, based on agency calculations of the sample labeling.

Among the key components of the redesigned section are statements that place any potential risks from the product in the context of the inherent risks of pregnancy and the risks of forgoing treatment.

The reg requires such description because "women of childbearing age and their health care providers overestimate the likelihood that drugs used in pregnancy will cause serious birth defects," which is "probably because of the thalidomide tragedy in the early 1960s."

That FDA is taking this opportunity, at least in part, as a reason to try to encourage drug use should be heartening to industry.

Carrying Risk Info For Two

The agency emphasizes the importance of improving risk communication throughout the reg. At a 1999 meeting of FDA's Reproductive Health Drugs Advisory Committee to assess the proposal, for example, "committee members cautioned against the use of phrases or terms such as 'use with caution,' 'crosses the placental barrier,' and 'probability' because the lay public and scientists define the terms very differently," the proposed reg states.

"One member also pointed out that all of the terms used to describe animal findings can be alarming to patients and providers," FDA notes.

"Committee members also objected to the heading 'Clinical Management Statement' because it suggested that the information is intended to dictate to health care providers how to manage their patients," the reg states. "They recommended that the heading be changed to 'Clinical Considerations' to clarify that the information is intended to assist health care providers and patients in making their own decisions."

Describing risk information in widely understood terms is one recommendation the agency proposes to improve comprehension. FDA recommends that sponsors use simpler terms, specifically, to describe developmental toxicities and birth defects in the fetal risk summary section of labeling, which must include a risk conclusion and narrative description.

For example, to describe developmental toxicities, the proposed rule uses ''developmental abnormalities.'' To describe dysmorphogenesis, the proposed rule uses ''structural anomalies,'' which includes malformations, deformations, and disruptions.

FDA concludes that "using a category system to characterize the risks of drug use during pregnancy would not be appropriate because of the complexity of medical decision-making about drug use during pregnancy." The existing requirement puts products into one of five categories (A, B, C, D and X).

The proposed reg states that the narrative description "is the best approach for summarizing such data in a comprehensive manner because the types of human data contributing to the assessment are variable and complex."

In keeping with congressional and agency interest in expanding the amount of safety data available about products, FDA encourages companies to search pregnancy registries in the absence or lack of sufficient clinical data on use in pregnant women.

To further distinguish the data, the proposed rule addresses two different situations: those where it is "sufficient," and those involving "other human data." The reg describes sufficient data as that from clinical trials, robust pregnancy exposure registries and other large-scale epidemiologic studies, or case series reporting a rare event.

The labeling would also be required to state if there are no data to assess risk, in addition to providing descriptions that would aid prescribing decisions for physicians.

Studies Of A Different Animal

However, in cases where human data are nonexistent, the reg addresses the use of animal findings to describe possible drug risks. In such instances, the label should clarify that the animal data can predict only that a risk exists.

Where the risk assessment is based solely on animal data, the rule "would require that the fetal risk summary component consist only of a risk conclusion, and not, in addition, a description of the effects found in animals. The risk would be followed by a cross reference to the data component and the effects found in animals would also be described there."

Additionally, it proposes that sponsors include the level of risk certainty and confidence limits of referenced studies.

The agency is seeking comment on whether labeling should be required to employ standardized statements when human data are not sufficient, among several aspects of the proposed reg (see ³ following story ).

The agency also expects to develop a guidance to outline how companies should categorize a product as low, medium or high risk in cases where only animal data are available, forgoing the narrative descriptions, Kweder said on a stakeholder call the day the reg was announced.

"We anticipate that we will be issuing guidance and probably holding some public workshop to help develop some general direction on how to frame that because it will be important that there be some consistency," Kweder said. Risk categorization based on animal data "is one of the areas that we ask for public comment on in the rule itself," she added.

The animal data guidance is one of several in the works to supplement the pregnancy reg. The agency is working to finalize the 2005 draft guidance "Clinical Lactation Studies - study design, data analysis and recommendations for labeling," as well as the 2004 draft "Pharmacokinetics in Pregnancy - study design, data analysis and impact on dosing and labeling."

The agency anticipates both will be finalized later this year.

A Footnote First?

The reg also suggests that labeling may start to include more outside information, especially interesting given the concerns about companies distributing off-label information through journal reprints.

The proposed reg includes a sample of what the new labeling might look like, and a hypothetical label for an asthma drug - Kappaate. The sample language includes a footnote for a "retrospective study on pregnant women exposed to Kappaate," in "Some Medical Journal."

FDA told "The Pink Sheet" that such footnotes would be "highly dependent on the quality of the references."

Another decision shows FDA's thinking that Rx safety information should be more broadly shared: Under FDA's current regulations, companies can omit the pregnancy section if the drug is not absorbed systematically and is not known to have a potential for indirect harm to the fetus, but the proposed rule would require that all drugs contain the section in the labeling.

Fewer Contraindications Coming

Unlike products that affect only the indicated patient, FDA must evaluate pregnancy drugs for safety risks to the mother and fetus, and therefore contraindications need to be handled differently.

The reg states: "in order to be contraindicated for use in pregnancy, the risk would have to clearly outweigh any therapeutic benefit either to the mother or to the fetus."

"Given that the mother's death would, depending on the gestational age of the fetus, result in the death of the fetus, the risk to the fetus from the drug would not necessarily outweigh the benefit to the mother."

In the past, the agency's existing practice has been to contraindicate a drug in its entirety for use in pregnancy if any indication is contraindicated, despite differing risk/benefit analyses for various uses - a point which raised concern among panelists in earlier discussion of the developing reg.

"Also current drug labeling has sometimes contraindicated a drug for use in pregnancy simply because it is reasonable to assume that a pregnant woman would not use or be prescribed that drug," FDA said.

Feedback from previous meetings suggested that a contraindication may give the impression that a drug causes severe events, such as fetal developmental abnormalities, even though it may not, which may lead some women to terminate otherwise wanted pregnancies, according to the reg.

Examples of such medications formerly contraindicated include oral contraceptives and fertility drugs.

- Carlene Olsen ([email protected])