Sunscreen Safety Framework Is FDA’s First Step, With More Tests Needed – NDAC

NDAC members agree with FDA’s proposed standards for evaluating the safety of sunscreen monograph ingredients, but suggest the agency add tests to evaluate the impact of long-term use, actual use and bioavailability in specific populations.

FDA’s proposed framework for evaluating the safety of sunscreen ingredients for the OTC monograph should include additional specific studies, such as an ingredient’s impact on children and effects from long-term use, and remain flexible to change as science and product innovation evolve, a panel of experts advise.

The agency also should require sunscreen manufacturers to perform specific safety and efficacy tests on final monograph products to account for differences in formulations, the Nonprescription Drug Advisory Committee recommended Sept. 5 at the conclusion of a two-day meeting. These tests should include interactions between combined approved ingredients and potentially different delivery vehicles.

The committee convened at FDA’s headquarters in Silver Spring, Md., to review the agency’s proposed standards to evaluate the safety of new sunscreen ingredients for inclusion in the OTC monograph, including human and non-clinical toxicology animal tests, and suggest changes as necessary. Unlike at other advisory committee meetings, FDA did not ask the panel of experts to vote on questions, but rather to provide suggestions and guidance (Also see "FDA Proposal For Increased Sunscreen Safety Testing On NDAC Agenda" - HBW Insight, 25 Aug, 2014.).

During the meeting’s first day, NDAC members cautioned FDA officials that existing OTC sunscreen monograph ingredients could be vulnerable to removal if the agency adopts more stringent evaluation standards (Also see "Existing Sunscreen Monograph Ingredients Could Fail Proposed Safety Standards" - HBW Insight, 5 Sep, 2014.).

FDA’s Proposed Safety Tests For Sunscreen Ingredients

The agency recommended sponsors provide this safety information to support ingredients’ status as GRASE, or generally recognized as safe and effective:

Human data:

• Dermal irritation and sensitization
• Phototoxicity and photoallergenicity
• Bioavailability
• Postmarketing adverse event reports

Nonclinical (toxicology) data

• Dermal and systemic carcinogenicity
• Developmental and reproductive toxicity (DART)
• Toxicokinetics

Many committee members recognized the proposed framework as a “thoughtful” first step, but as one member noted, “the devil is in the details,” and some details need to be fleshed out.

“All the things that were recommended in the FDA framework, I think, should happen,” but the agency needs to drill down farther to explain what it will do with the additional data, said committee member Judith Kramer, professor emerita of medicine at Duke University School of Medicine.

For example, she lauded FDA’s inclusion in the framework of maximal use studies to understand the bioavailability of sunscreen ingredients, but asked what the agency planned to do with that data. If studies show the ingredient is bioavailable, additional studies likely would be needed to identify the impact of the absorption over time and if it differs among populations, she said.

Kramer recommended the bioavailability be examined in children and the elderly because they represent the “extremes for safety,” considering they are vulnerable groups and skin becomes less permeable with age.

She recognized that historically, testing these groups and pregnant women has been viewed as unethical. However, she justified her potentially controversial recommendation to test the products on children by noting they have the highest ratio of dose to body weight because of their size. She also noted children as young as six months already use the products and the alternative to not testing this group in a scientific way is to continue to expose the total population to potential risk.

Geoffrey Rosenthal, professor of pediatrics and epidemiology at the University Of Maryland School Of Medicine agreed, noting “it is not only ethically permissible, but ethically required to do some of these studies in children.”

Testing the product in pregnant women also is important to determine if the ingredients are being absorbed and passed to infants in breast milk, members noted.

Long-term Tests Needed

Testing children also would open the door for FDA to conduct long-term use studies of ingredients, as committee members recommend.

“It bothers me these things have been available for 40 years and I recommended them for nearly 40 years, and yet at this meeting was the first time I began to realize they are systematically absorbed and there could be long-term consequences because nobody has looked,” said David Margolis, a professor of dermatology and epidemiology at the Perelman School of Medicine at the University of Pennsylvania.

“What is missing from the framework … is the true safety of these things long-term,” which could be gathered through prospective studies following current sunscreen users or through retrospective studies, Margolis added.

Long-term studies also should take into account the actual amount and frequency of sunscreen consumers’ use, said June Robinson, a dermatology research professor at Northwestern University Feinberg School of Medicine.

Robinson underscored the surprise many committee members expressed when they learned manufacturers routinely test a dose 2 mg/cm2 of sunscreen when evaluating safety and efficacy, but most consumers only use 30% of this amount. She suggested manufacturers should amend this to test more realistic amounts.

Margolis also raised concerns about FDA’s proposal to use rat and other animals to study sunscreen ingredients’ bioavailability and toxicology. He said inducing skin cancer in rodents is difficult and rodent skin is penetrated differently than human skin, which could impact how test results translate to humans.

“I would ask that people be careful about the models they suggest,” Margolis said.

Flexibility Vital To Long-Term Success

While adding these tests will strengthen FDA’s framework, the standards should not be so prescriptive that they stifle innovation or are unable to evolve with scientific advancements, committee members agreed.

They explained that the framework and corresponding regulations should not be so onerous that they make life impossible for industry to the point that firms stop making sunscreen products.

One inordinately tall order would be the recommendation by some members that FDA require manufacturers to conduct standard safety tests proposed in the framework on their final formulations.

The members acknowledged that industry might oppose such a potentially redundant and resource-intensive requirement, but it would enable firms to be confident about the products’ safety in light of the addition of active and inactive ingredients.

Such a requirement also would allow manufacturers to test whether the delivery vehicle, such as lotions, gels or sprays, impacts the final products’ safety or efficacy.

FDA officials requested guidance on how to evaluate the impact of delivery vehicles, but also noted the agency is developing separate regulations for new sunscreen delivery formats.

Considering this, members recommended the framework be flexible enough to account for the many other moving parts of FDA’s sunscreen regulation.