FDA is seeking to move ahead quickly with new regulations for pregnancy labeling following the release of the physician labeling final rule.

Proposed changes would better characterize risk information and eliminate the letter system used to categorize the safety and risk associated with prescription drug use during pregnancy.

Our goal is "to describe things in descriptive text, instead of just a letter system, to avoid the current lifting of a single letter and over-simplification of data," Office of New Drugs Deputy Director Sandra Kweder said May 3 at a Drug Information Association meeting on drug exposure during pregnancy.

Changes to the pregnancy section have been in the works since 1997 when FDA's Prescription Pregnancy Labeling Task Force first addressed the issue (¹ Also see "FDA Rx pregnancy labeling guidance under development; public hearing planned." - Pink Sheet, 4 August, 1997., T&G-8). Following a Part 15 hearing, the proposal was discussed at several advisory committees in 1999 and 2000.

The status of the changes "has been languishing," Kweder acknowledged. "We've been kind of done with it, waiting for the administration to take note of it."

Updates to the pregnancy section were omitted from the final physician labeling rule issued in January so that work on the separate reg could continue.

FDA does not expect that changes to the pregnancy section will impact the new highlights section of labeling, which is the most prominent feature of the final rule (² Also see "Unfinished Labeling Business: Pregnancy, In Vitro Data, Containers" - Pink Sheet, 13 February, 2006., p. 29).

"Whenever you're talking about regulation, every administration only has what I call so much regulatory capital," Kweder said. "Regulations are not looked upon warmly by most administrations, at least not this one. It's starting to change; at least we think it's possible."

FDA hopes to publish a proposed rule by the end of 2006.

Kweder emphasized that the pregnancy language in labeling needs to provide well characterized risk information.

"The letter categories and the boiler plate language that accompanies them are not clinically relevant or particularly informative," she noted. "The categories are also quite simplistic and it's hard to fit all the potential clinical situations of risk into five letter grades."

"Our label without letters model will include a summary risk assessment with some standardized risk statement and will incorporate both human and animal data," Kweder said.

Current labeling fails to communicate and interpret data relevant to patients and their healthcare providers.

"Where there are data, often those data don't make it to the most widely available source of information, which is the label," Kweder said.

The exclusion of broader data omits key areas of importance in the treatment of pregnant women.

For example, "the issue of inadvertent exposures is absolutely not addressed and we have heard loud and clear from the public that this is an enormous area of concern to clinicians," Kweder noted.

The deputy director also highlighted the responsibility of FDA to interpret data for the public.

"We tell the clinician what to watch for in the area of safety, how worried to be. We can't divorce ourselves from that responsibility in this area," she said. "We don't do that for the indication of the drug, we tell the clinician what to think about the data."

The lack of publicly available data coupled with preconceived notions about prescription drug use during pregnancy furthers the difficulties associated with treating pregnant women.

"There is this prevailing belief that pregnant women should avoid taking prescriptions....The translation of that societal belief is that even at the expense of her own health, in many cases, a pregnant woman will not take a medicine," Kweder explained.

The proposed pregnancy label will alleviate some of the problems associated with the current system by separating clinical advice from communication of risk information and data.

"We are going to require that clinical considerations be taken into account in the narrative text including factors that the clinician might consider in applying a risk assessment to patient care, such as what the benefits of a particular product might be if it's relevant." Kweder said.

Changing the label, however, will not obviate the need for additional data.

"We need more, better data," Kweder said. "Careful, prospective, numerator and denominator outcome data, robust epidemiology studies and clinical pharmacology data, which we believe can teach us a lot about exposure and risk [and] information about dose in pregnancy and metabolism."

FDA has put forth several guidance documents related to pregnancy in an effort to facilitate data collection (³ Also see "Pregnancy Registry Guidance Could Stress Collaboration, Tackle HIPAA" - Pink Sheet, 31 May, 2004., p. 33).

Topics covered by the guidances include establishing pregnancy registries, assessing human reproductive and developmental toxicities, evaluating human pregnancy outcomes data and conducting clinical pharmacology studies in pregnancy.

The guidance on establishing registries was written "because there is nothing in the literature that describes how to conduct a registry," Kweder explained.

Also speaking at the DIA meeting, National Center on Birth Defects and Developmental Disabilities Medical Officer Janet Cragan outlined when registries should be considered and when post-marketing surveillance is warranted.

Among other reasons, post-marketing surveillance is indicated when there is potential for inadvertent exposure or when a drug is a known teratogen, a new molecular entity or widely used among women of childbearing age.

Priorities for initial surveillance do not include drugs that are indicated for topical use or that have been widely used in pregnant women over a long period of time.

While ideally FDA would like to know the risks of all drugs used during pregnancy, Kweder noted "we don't believe registries are a panacea for collecting information on [the] safety of drugs in pregnancy."

"The reality is that there are insufficient resources and there are insufficient methods to monitor all the drugs, so you do have to prioritize," Cragan said.

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