Industry trade groups ask FDA to “significantly revise” its draft guidance on safety and effectiveness data needed for OTC sunscreen ingredients and produce a “modern version based on advances in toxicological risk assessment.”

“We believe the draft guidance proposes a framework that is not reflective of the current state-of-art in ingredient safety assessment,” say the Consumer Healthcare Products Association and the Personal Care Products Council in Feb. 22 comments to FDA.

The draft guidance, “Over-the-Counter Sunscreens: Safety and Effectiveness Data Draft Guidance for Industry,” is one of four FDA released in November, meeting a deadline set by the Sunscreen Innovation Act. The act passed November 2014 also requires the agency to finalize the guidances in November this year.

The draft summarizes FDA’s thinking on the scientific evidence needed to show sunscreen active ingredients are generally regarded as safe and effective (GRASE) and should be added to the OTC drug monograph through time and extent applications. A time and extent (TEA) application is a procedure to incorporate a new product or a product condition (such as an active ingredient) into a monograph on a consumer drug category.

In the draft, the agency evaluates clinical safety data for potential OTC sunscreen ingredients as it does ingredients for other topical products for chronic use and urges sponsors to meet the customary safety data requirements for chronic-use cutaneous drug products seeking approval in the new drug application process.

FDA outlined the type of data necessary, including topical safety studies exploring irritation, sensitization and photo-safety, as well as bioavailability data and information about adverse events observed in clinical trials.

The draft also highlights areas where animal data is necessary, including when a sunscreen active ingredient is found to be absorbed.

The deadline was Jan. 22 for comments on the other draft guidances – discussing the advisory committee process; withdrawing TEAs; and the content and format of TEAs ([A#05160215006] and [A#05160125010]).

FDA said in November it was most interested in feedback on the safety and effectiveness data draft guidance and in January extended the comment period for a month ([A#05151123013]).

'Holistic' Approach To 'Robust' Evaluation

The trade groups ask FDA for new guidance that considers current approaches in toxicological risk assessment that are “appropriate and applicable for all chemical exposures, whether from food, drugs, cosmetic or environmental contaminants.”

They argue the discipline of toxicology is experiencing an “exciting evolution” from an observational discipline to a mechanistic-based” science that combines in vitro and in vivo data and predictions determined via computer simulation – in silico – to evaluate quantitative risk and assess safety.

“This transformational change is driven by many factors including the overwhelming need to toxicologically evaluate the universe of chemicals using limited resources and in many cases doing away with animal tests that may not be predictive of human toxicity,” they add.

CHPA and PCPC urge FDA to adopt a more flexible approach in the consideration of a testing data set in demonstrating GRASE status for a TEA sunscreen active ingredient, as it is in line with 21st century toxicology’s “holistic” approach to developing “robust” evaluations of substances.

They point to examples of the draft failing to incorporate modern approaches and not allowing for flexibility.

In the area of nonclinical safety testing, FDA recommended that to support OTC sunscreen active ingredients, TEA applicants should conduct a two-year dermal carcinogenicity study of applying a product to the skin of mice or rats as well as study the effects of systemic exposure if the dermal studies show potential skin penetration.

However, the trade groups say the requirement for both is “academic and unnecessary.”

“In the presence of a carcinogenicity alert and evidence of dermal penetration, only one relevant route of exposure for carcinogenicity study needs to be considered. Depending on the available hazard data, a decision between a dermal carcinogenicity study needs to be made instead of requesting studies for both routes.”

In testing for carcinogenicity in maximal usage trials, which test for adequate safety margins for actives that absorb through skin, FDA recommends that with ingredients that have absorption properties, sponsors conduct MUsT in young children, since children have a larger ratio of surface to body volume and therefore higher systemic exposure to ingredients.

The groups criticize the suggestion. “We consider it unnecessary to conduct MUsT or other studies in young children for TEA sunscreen active ingredients. While full skin development continues through the first year of life, the stratum corneum barrier is sufficient at birth,” they say.

CHPA and PCPC also disagree with FDA's recommendation for final formulation testing to ensure the effectiveness of OTC sunscreen products, “namely testing for SPF value as well as broad spectrum protection and water resistance, where those attributes are claimed in product labels.”

In the draft guidance, the agency says it expects conditions of marketing for sunscreen active ingredients “would require manufacturers to perform in vitro permeation testing before marketing each new formulation.”

The groups say the recommendation is unnecessary. “Such testing of every formulation would not be needed if ranges of penetration with different types of vehicles are established or reliably predicted through modeling and a sufficiently wide margin of safety exists to encompass such variations in predicated internal exposures," according to the comments.

“Through this approach, changes in dermal penetration would not affect the safety determination. This would return the focus to developing sunscreen products with greater acceptability, with a goal of motivating more consumers to use sunscreens appropriately.”

They also countered FDA’s numerous recommendations for animal testing, noting in some cases it is simply not necessary given alternative approaches often available.

“While we recognize that in vitro alternatives do not exist for all toxicological endpoints, there is growing recognition that incomplete data sets can be supplemented with" in vitro or in silico data. "With the application of appropriate uncertainty factors, a level of confidence in the final risk assessment comparable to that from traditional animal studies can be achieved,” according to the comments.

The groups suggest, for example, “a quantitative risk assessment approach, that incorporates up-to-date" in vitro data and physiologically-based pharmacokinetics modeling or other computer simulation approaches as well as mechanistic and mode of action data, "would reduce unnecessary testing that does not truly add a public health benefit.”

CHPA and PCPC give numerous other examples of where they say FDA’s methods are out-of-date, unnecessary or overlook alternative approaches.

“The notion that the studies presented in the guidance are needed to make a safety judgment is, in our view, inconsistent with the direction being taken by toxicological communities today,” they say.

The groups state the guidance must be more informative in some areas. For example, while it is clear in terms of the agency’s proposed study requirements for TEA sunscreen active ingredients, it does not articulate the methods that should be used, or the criteria for success.

“To explain why some of these toxicological endpoint studies are needed, the agency should communicate the methodology to be used to determine from the toxicology studies that a TEA sunscreen active ingredient is [GRASE],” the groups note.

“Clarity is provided in other regions of the world for the process and methods whereby human safety and market acceptability are determined from toxicological endpoints. In the absence of such clarity, the guidance serves only as a checklist without perspective or judgment applied to the interpretation of the data."

Update NDAC, Too

They also argue that discussions by FDA's Nonprescription Drugs Advisory Committee have "provided only a narrow view of safety assessment."

The panel at a September 2014 NDAC meeting on sunscreen ingredient safety, for instance, did not include members or input from toxicologists with specific expertise in emerging areas relevant to safety assessment, such as pharmacokinetics and toxicogenomics, say the trade groups.

"Additional input from such individuals is needed to provide current thinking in these important areas. This would include scientists from academia, other regulatory agencies, other offices within the FDA and from industry," according to the comments, which note that the trade groups suggested in separate comments on SIA guidance that FDA "look broadly for expertise that is specific to the questions" that an NDAC will consider ([A#05160125010]).

“It is our hope that FDA continues to update its thinking (and the Guidance) as the science evolves,” say the trade groups, urging the agency to meet in a scientific forum with industry stakeholders “to determine how the guidance can incorporate flexibility appropriate and in keeping with” modern toxicology.

The comments echo some sentiments of frustrated TEA sponsors, including [L'Oreal USA Inc.] and BASF Corp. that have urged the agency to consider the overall weight of firms' safety evidence rather than focusing on isolated study shortcomings and to exercise greater flexibility in its evaluations.

L’Oreal and BASF are among the sponsors of eight sunscreen TEAS that FDA in early 2015 said had insufficient data to show GRASE ([A#05140908013]).

[Editor's note: This story is also published in "The Tan Sheet." "The Pink Sheet" DAILY brings selected complementary coverage from sister publications to our subscribers.]

Sunscreen Trade Groups Urge 'Modern' Risk Assessments For Ingredients

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