GAITHERSBURG, Md. -- An FDA advisory committee voted 16-0 on Friday that a decades-old topical retinoid for acne was safe for use over the counter, marking a first-in-class switch. However the panel remains divided on the question of labeling.

The FDA's Nonprescription Drugs Advisory Committee (NDAC) found that the safety profile and the totality of the data for adapalene gel .01% were adequate to allow the product to be sold over-the-counter.

Adapalene (Differin) is a topical retinoid -- vitamin A derivative -- manufactured by the Swiss-based Galderma, and indicated for the treatment of acne in children age 12 and older.

The focal point of the panel's discussion was the product's safety -- in particular, its potential for use among women who are pregnant or may become pregnant. The safety risk is weighed against the product's potential for benefiting a large group: about 85% of teenagers are affected by acne as are about 12% of adult women, according to the FDA.

"As a topical retinoid, adapalene has been shown to be teratogenic when given orally in animals at doses above those that can be achieved with dermal distribution in humans," Theresa Michele, MD, director of the FDA's Division of Nonprescription Drug Products, said in her opening remarks.

However, the current prescription label does not include a contraindication for use in pregnancy, she noted.

"This would be the first time we've considered placing over-the-counter a product that does have a significant toxicology signal for teratogenicity, and as such what we're asking you to weigh is where do you set that bar? What's an appropriate level of risk in the over-the-counter setting, given the absorption profile that we see for adapalene?"

Adapalene received approval in the U.S. in 1996. It is currently registered in 82 countries, as of July 2014, according to FDA briefing documents. Only Russia has allowed OTC marketing of adapalene 0.1% gel.

The panel's vote seemed to reflect its agreement with the sponsor's argument that the risk of teratogenicity was "low with a very wide margin of safety."

Stephen Harris, PhD, president of the Stephen B. Harris Group in San Diego, Calif., an expert in developmental and reproductive toxicology and a committee member, said, "When you look at all the potential signals that we look for in developmental and reproductive toxicology studies to determine a human risk, I see none."

Harris, in explaining his support for the OTC switch, acknowledged that while animal studies at high dose levels (25 mg/kg and 60 mg/kg) did reveal malformations, noted, "We can create problems, when we go to excessive doses. In this case, these studies satisfy my concerns regarding reproductive risk. "

The FDA's technical experts said that based on pharmacokinetic studies in animals and maximal-use data in humans, the margin of safety is "at last 70-fold for dermal application." Yet, staff also noted that because animal studies cannot always accurately predict human effects, true "human sensitivity is unknown."

While there was consensus on the product's safety, the committee did not reach agreement on the issue of labeling.

Some members urged removal of a warning for pregnant women to consult their primary care providers.

"We either say it's safe or we say it's not safe," said Sarah Gloria Obican, MD, an assistant professor of maternal fetal medicine at the University of South Florida, in Tampa. She said that including "misinformation" in the labeling could have unintended consequences, including women electing to have abortions because they fear fetal abnormalities.

Others urged strengthening the warning around pregnancy, and at least one panelist suggested a contraindication.

In addition, some panelists suggested that the label have a stronger warning of sensitivity to sunlight, and include more specifics about the duration of use.

Prior to the meeting, the sponsor submitted three consumer studies to the FDA: a study of label comprehension, a self-selecting study focused on pregnant and breastfeeding women, and an actual-use study.

The label-comprehension study, which included 586 participants, met its primary endpoints for consumers understanding of "use once daily" and "do not use on damaged skin." However, the agency was disappointed that the sponsor did not test label comprehension of the pregnancy warning.

The actual-use study, completed by 938 participants, was also successful in demonstrating that most users would use the product once daily, and for acne treatment only.

However, the sponsor failed to meet its endpoints in a study of pregnant and breastfeeding women, which tested whether participants would consult a healthcare professional prior to use, as product safety information recommends.

The FDA is not required to follow the advice of its advisory committees, but it often does.