Pregnancy Labeling Needs Clearer, More Consistent Language, US FDA Panel Says

Language used to describe drug effects on pregnancy and lactation is ambiguous, complex and not useful to prescribers, advisors say, also urging FDA to use graphics or rating scales to convey the strength of the animal and human data on use during pregnancy.

The US FDA should use more consistent language, as well as graphics or rating systems, to convey information about drug effects during pregnancy and lactation in product labeling, advisory committee members said March 6.

The agency's Risk Communication Advisory Committee suggested the agency needs to rethink its application of the December 2014 Pregnancy and Lactation Labeling Rule (PLLR), which replaced the longstanding, letter-based system for classifying a drug's risks in pregnancy with risk summaries and a discussion of supporting data.

The panel questioned how useful the new format has been in communicating data about the effects in pregnancy and lactation, and the uncertainties associated with such data, to physicians and patients who must decide whether or not to use a drug during or immediately after pregnancy.

"What we don't know, say we don't know. When the data is poor, say the data is poor. Be clear, and use consistent and plain language that can be easily skimmed particularly in a short doctor's appointment." –  Patient representative Joniak-Grant

Advisory committee members found the some of the language used in the new labeling to be overly ambiguous, complex and not useful to prescribers.

They called on FDA to do a better job explaining the strength of the available animal and human data on a drug's effects in pregnancy and lactation, and they suggested that labeling include baseline and disease-specific risk information, such as for miscarriage rates.

In addition, committee members urged that labeling be written in plain language and undergo end user testing.

Patient representative Elizabeth Joniak-Grant was among many panelists who urged the agency to take a more straightforward, consistent approach to explaining the often-limited data available on drug effects in pregnancy and lactation.

"What we don't know, say we don't know," Joniak-Grant said. "When the data is poor, say the data is poor. Be clear, and use consistent and plain language that can be easily skimmed particularly in a short doctor's appointment."

If FDA adopts the panel's suggestions, labeling for older products that must soon convert to the PLLR format may look very different than the initial round of products subject to the rule.

Performance Check At 500 Labels

The PLLR took immediate effect on June 30, 2015 for drug and biologic product applications submitted on or after that date.

Applications approved between June 30, 2001 and June 30, 2015 had three to five years to meet the new requirements, meaning that PLLR submissions for these products are due in 2018-2020. The agency anticipates it will receive more than 1,500 PLLR submissions for existing products over the next few years.  (Also see "Pregnancy Labeling: US FDA Ponders Whether Changes Needed To Overcome Risk Misperceptions" - Pink Sheet, 27 Feb, 2018.)

For products facing labeling conversion by 2020, the review divisions have been asked to consider whether there are some that should be prioritized for early focus, or some that should be delayed to ensure that all labels across a class are converted simultaneously, said Lynne Yao, director of the Division of Pediatric and Maternal Health (DPMH).

Currently, about 500 products have labeling in the PLLR format. "We're 500 labelings into this, and we don't know if we're doing what we have been told we should be doing under the intent and spirit of the rule," Yao said.

Industry Sees Consistency Problems

Giving an industry perspective on the early experience with the PLLR format, guest speaker Traci Lee, director of labeling in global regulatory affairs at GlaxoSmithKline PLC, raised concerns about differences among review divisions in how the new format has been applied.

"Across the different review divisions … there's different thresholds for including the data," Lee said. "Generally, we've seen that limited information has been accepted in the clinical considerations section or it was streamlined and only the best data was taken."

More consistent consultations between review divisions and DPMH might be helpful to addressing these inconsistencies among review divisions, she suggested. "It seems in the few cases where they [DPMH] were consulted, more relevant information seems to have made it in the label," she said.

Lee also asked whether standards governing inclusion of data in PLLR labeling could be created to help guide industry.

Four Phrases Bring Objections

FDA sought comments on the adequacy and utility of four phrases currently used in PLLR risk summaries:

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

Leyla Sahin, a senior medical officer in DPMH, said these phrases are representative of the types of standard statements FDA has been incorporating in PLLR labeling in light of complaints about variations across drug products and disease areas. "We've taken those comments into consideration," Sahin said. "We have been trying to develop more consistent type language."

However, the panelists were not enthused about any of the phrases, finding them to be too ambiguous, lacking in specificity and, in some cases, suggesting a negative connotation. For example, Joniak-Grant said the phrase "have not reported a clear association" potentially implies there may be an association.

The committee's industry representative, Gerard Nahum, vice president of global development for general medicine at Bayer HealthCare Pharmaceuticals AG, said he disliked the term "limited data" because "it applies to all circumstances always."

He suggested characterizing data as either "sufficient" or "insufficient" to make a conclusion about a specific risk during pregnancy.

Panel chair Susan Blalock, vice chair of the Division of Pharmaceutical Outcomes and Policy at the University of North Carolina, also saw interpretability problems with the statements about available data either being "not sufficient to inform the risk" or not reporting a "clear association."

"I'm virtually certain that if you got 10 clinicians in here without experience in this area, that they would interpret those phrases in 10 different ways," Blalock aid.

Using similar phrases would help bring more consistency to labeling, Joniak-Grant said. "Something just even as simple as 'data suggests there is an association,' 'the data suggests it's highly likely there is an association,' 'the data suggests there may be an association,'" she said.

"Structured and consistent language could greatly improve labeling," said Anne Lyerly, associate director at the Center for Bioethics and a research professor in obstetrics/gynecology at the University of North Carolina, Chapel Hill.

Lyerly was among those who favored adding a statement in labeling explaining that a drug's approval in adults encompasses pregnant women, absent a specific contraindication in such patients.

"I also think that communicating the view of the FDA that the drug is approved in general adult populations, which includes pregnant women" would be helpful, Lyerly said, because "I just do not think that doctors know that."

Seeking A Simpler Approach

On the matter of how effective the PLLR has been in conveying safety evidence in pregnancy, panelists were struck by results from an American Academy of Allergy, Asthma and Immunology survey in which 76% of respondents said they still use the pregnancy risk letter category, instead of the PLLR risk summary, when making prescribing decisions. In addition, more than half of the respondents said the new labeling format did not bring more meaningful information to them or their patients compared to the old format.

Some panelists bemoaned the shift away from a simple, letter-based system that was easy for prescribers to remember and understand.

"I definitely appreciate that there were problems with the old system, but I do wonder a little bit if you've thrown the baby out with the bathwater," Blalock said. "People thought they understood the letters. They didn't understand them the way that you wanted them to, but I worry that something was lost in getting rid of them."

"The old system was horrible," Yao said. "It was incorrect, it was inaccurate, and people misunderstood the system and used it incorrectly." Instead, she asked what more FDA could do within the current PLLR framework to ensure that data on effects in pregnancy are better communicated.

Some panelists suggested FDA should attempt to convey the strength of the animal and human data through graphics, such as a forest plot, or rating scales, such as a star system or a visual analog scale ranging from 0 to 10. Another proposal referenced a National Academies' six-level rating scale for tobacco products, ranging from "no available evidence" to "substantial evidence."