Pregnancy Labeling: US FDA Ponders Whether Changes Needed To Overcome Risk Misperceptions

Risk Communication Advisory Committee will opine on impact that Pregnancy and Lactation Labeling Rule has had in conveying safety evidence useful to making prescribing decisions for pregnant patients and whether current labeling language can be improved upon.

The US FDA is seeking advisory committee help in deciding whether changes to drug labeling language are needed to better convey the risks of products used during pregnancy.

The agency's Risk Communication Advisory Committee will meet March 5-6 to discuss the effectiveness of communications about risk information on fetal effects under the Pregnancy and Lactation Labeling Rule (PLLR).

More than 500 products have been converted to the new labeling format, but fewer than 25% of these include human data on use during pregnancy.

The panel also will discuss the perception of risk and factors that are important to patients and prescribers in their treatment decision-making, approaches to effectively communicate risk, and strategies for minimizing unintended adverse consequences of risk communication.

Panelists will assess the impact that the PLLR has had to date and consider and whether further adjustments are needed as the labeling format is applied to more than 1,500 drug products over the next three years.

PLLR Experience To Date And To Come

The PLLR, which was finalized in December 2014, eliminated the longstanding, letter-based system for classifying a drug's risks in pregnancy. It replaced this approach with narrative summaries of risk during pregnancy and lactation, and a discussion of the supporting data. The labeling format also included a new section specific to females and males of reproductive potential. (Also see "Pregnancy Labeling Gets A New Look" - Pink Sheet, 8 Dec, 2014.)

The rule took effect June 30, 2015 but had a staggered implementation, taking immediate effect only for applications submitted on or after that date. Applications approved between June 30, 2001 to June 30, 2015 had three to five years to meet the new requirements, depending upon their approval date.

The format does not apply to applications approved prior to June 30, 2001. However, FDA has encouraged voluntary compliance, and sponsors of these older products must remove the pregnancy letter category from their labeling by June 30, 2018. (Also see "Pregnancy Labeling Changes May Spur Research, FDA Says" - Pink Sheet, 3 Dec, 2014.)

FDA's Feb. 16 meeting memorandum includes metrics on the PLLR's implementation to date. (See box)

PLLR Format Labeling Conversions

Years	Number Of Labels Converted (Actual Or Estimated)^1
2016-2017	>500
2018	~450
2019	~800
2020	~300

¹ Estimates do not include conversion of labeling for numerous generic drugs or labeling of prescription drugs not already in the Physician Labeling Rule format.

Under the PLLR, the pregnancy subsection of labeling includes information on pregnancy exposure registries (if applicable), a risk summary, clinical considerations (if data are available), and concise summaries of any human and animal data that support the risk summary and clinical considerations.

"The agency recognizes the challenges in providing the risk information as intended with the PLLR when there are limited available human data to inform about the risk/benefit of the use of a drug during pregnancy," the briefing document states. "Of the over 500 products that have been converted to PLLR format, fewer than 25% include human data."

"The lack of interpretable human data combined with potential risk misperceptions can impact appropriate risk/benefit decisions about the use of a drug during pregnancy," the agency said.

Overcoming Risk Misperceptions

In pregnancy, the considerations involved in deciding whether to use a drug should balance the risks and benefits of treatment versus risks to the pregnant woman and fetus of either non-treatment or a different treatment, FDA said.

"However, such a benefit/risk approach is challenging in pregnancy due to various factors, such as societal and familial expectations and personal maternal desire to do what is best for her pregnancy," the agency said. "In reality, the decision to receive treatment is considerably influenced by perceived risks of the treatment, which play an important role in prescribers’ decision to recommend treatment and pregnant women’s acceptance of such treatment."

The briefing document includes a summary of published literature on risk perception of drugs in pregnancy, including studies conducted in the US involving influenza vaccines. The studies identified concerns among pregnant women about the safety of influenza vaccines even though they are recommended. "Of note, the women's knowledge that influenza disease caused by pandemic (H1N1) 2009 virus was a serious, potentially fatal illness did not influence the decision to receive the vaccine," FDA said.

The agency also reviewed studies on risk perceptions for various prescription and over-the-counter drugs. In one study, respondents generally believed there was an increased risk of birth defects with all medications queried, and sedatives/anxiolytics and antidepressants were deemed slightly riskier than thalidomide, a known teratogen.

In another study, researchers concluded that pregnant women believed a drug was harmful even though it was described as safe in scientific terms on the labeling. Health professionals also rated the drug has having some risk.

Points For Discussion

Panelists will be asked to discuss their interpretation of the following phrases currently used in the PLLR risk summary "and provide any suggestions for improvement, if applicable":

• "Adverse developmental outcome;"
• "Limited data;"
• "Available data are not sufficient to inform the risk;" and
• "Available data have not reported a clear association."

In addition, FDA intends to ask the panel to discuss how effective the PLLR has been in conveying safety evidence in pregnancy that is useful to benefit/risk decision-making and to recommend strategies for improving risk communication that comply with PLLR requirements.

The agency seeks input on the best way to communicate certain types of data, such as inconsistent observational study findings, in product labeling, and on communication strategies that it can use to maintain a balanced benefit/risk assessment to minimize unintended consequences.