FDA provides insight into its expectations for safety and effectiveness data supporting sunscreen ingredient GRASE determinations in a draft guidance released on deadline and 10 months after the agency's tentative rejection of eight related time and extent applications.

Prepared for publication in the Nov. 23 Federal Register, "Over-the-Counter Sunscreens: Safety and Effectiveness Data Guidance for Industry" summarizes FDA's "current thinking" on the scientific evidence needed to add sunscreen active ingredients to the OTC drug monograph through the TEA pathway.

The document is one of four FDA draft guidances released Nov. 20 on the subject of nonprescription sunscreen active ingredients and the one on which the agency is most interested in receiving feedback.

"The GRASE review for active ingredients takes into account the fact that the ingredient, if found GRASE, may be included in a variety of formulations that will be marketed without product-specific review and approval," FDA notes.

FDA's Center for Drug Evaluation and Research met the one-year deadline set by the Sunscreen Innovation for guidance on the agency's safety and effectiveness data requirements for sunscreen actives. Passed in late 2014, the SIA implemented a concrete time line for FDA's review of sunscreen TEAs in the interest of speeding new UV filters to market ([A#02141124001]).

Stakeholders – including the Public Access to SunScreens coalition, which was instrumental in the legislation's conception and passage – have been disheartened by results to date. Early in 2015, FDA issued orders finding all eight sunscreen TEAs in its review queue not GRASE due to insufficient data, though it invited sponsors to follow up with additional evidence Also see "PASS Reacts To Sunscreen TEA Denials: Has FDA ‘Moved The Goal Post’?" - HBW Insight, 27 February, 2015..

Frustrated TEA sponsors, including L'Oreal USA, Inc. and BASF AG, have urged the agency to consider the overall weight of their safety evidence, rather than fixating on isolated study shortcomings, and to exercise greater flexibility in its evaluations ([A#02150323007]).

Meanwhile, FDA has maintained that the SIA did nothing to alter GRASE (generally recognized as safe and effective) requirements and suggested that GRASE criteria represent an even higher standard than that for new drug applications.

The agency alludes to the rationale behind that position in its draft guidance.

"Unlike the review of sunscreen products under the new drug approval process, for which premarketing testing focuses on individual product formulations, the GRASE review for active ingredients takes into account the fact that the ingredient, if found GRASE, may be included in a variety of formulations that will be marketed without product-specific review and approval," FDA notes.

In essence, the agency is less comfortable signing off on the safety of a drug ingredient that stands to be used into any number of formulations, potentially interacting with a wide variety of other drug ingredients and vehicle components, compared with a new substance being evaluated within a specified context under an NDA.

FDA says the newly issued draft guidance "will help sponsors identify and obtain the safety and effectiveness data needed to show that sunscreen active ingredients are GRASE for use in nonprescription sunscreens."

According to the document, FDA approaches the clinical safety evaluation of potential OTC sunscreen active ingredients as it would other topical products for chronic use. TEA sponsors should seek to meet the customary safety data requirements for chronic-use cutaneous drug products seeking new drug approval, it says.

With that in mind, companies should provide topical safety studies exploring irritation, sensitization and photosafety, as well as bioavailability (absorption) data and information about adverse events observed in clinical trials.

In a same-day post to its website discussing the guidance, FDA's Theresa Michele, director of the Center for Drug Evaluation and Research’s Division of Nonprescription Drug Products, provides further explanation "from our perspective."

According to Michele, "we are recommending skin safety studies to determine if products containing a certain active ingredient could cause irritation or rashes, or reactions when exposed to the sun. … In addition, we are recommending studies to obtain pharmacology data in humans and animals to assess how much, if any, of the active ingredient is absorbed into the body when applied to skin."

She continues: "If the active ingredient is not absorbed above a specified amount, we ask for minimal data in terms of additional studies, such as looking at its effects on the skin of animals. If a sunscreen active ingredient is found to be absorbed, then we will ask for additional animal data including whether the active ingredient causes cancer, reproductive harm or endocrine effects once it gets into the body."

"As manufacturers review this guidance, we ask that they work on studies to address any safety data gaps for each of their sunscreen active ingredients being evaluated under the SIA. We also encourage sponsors to come in and talk to us so that we can address any questions they may have." – FDA's Theresa Michele

In addition to covering those points, firms should include in their submissions an evaluation of reported adverse events associated with commercialized sunscreen products in foreign markets, the agency notes.

AE information has been among data gaps commonly cited by FDA in meetings with TEA sponsors. While the agency has acknowledged the challenges implicit in obtaining such information, particularly given that regulatory systems in markets outside of the US do not always have established mechanisms for reporting adverse experiences, FDA maintains that a robustly characterized AE profile is essential ([A#02150112004]).

FDA goes into its expectations for clinical safety evidence in greater detail in the guidance.

Data Sought For Potential Long-Term Effects

In its consideration of nonclinical safety evidence for sunscreen active ingredients, FDA says it takes into account that sunscreen ingredients eligible for inclusion in the OTC monograph have been marketed to a material extent and for a material time in markets outside of the US, which has bearing on the agency's review focus.

While FDA expects NDAs for chronic-use cutaneous drug products to include comprehensive nonclinical pharmacology and toxicology safety testing, its primary concerns in evaluating potential OTC sunscreen ingredients relate to potential long-term adverse effects "or effects not otherwise readily detected from human use (i.e., carcinogenicity and reproductive toxicity)."

The agency says substances that raise flags regarding other long-term effects, such as hormonal disruption, may require additional testing beyond what is recommended in the guidance document.

Additional detail on recommended testing protocols and study endpoints is provided.

The draft guidance also addresses effectiveness testing to demonstrate an OTC candidate ingredient's capacity to prevent sunburn. Another section discusses initial characterization of sunscreen active ingredients subject to review, which entails providing information that will inform the agency's final orders, including known interactions with other UV filters or commonly used sunscreen vehicle components and particle size information for micronized or nanoscale active ingredients, among other considerations.

Anticipated Final Formulation Testing

FDA also offers its current thinking about an approach to safety-related final formulation testing likely to be adopted by the agency down the road.

"We anticipate that additional safety-related final formulation testing will be necessary to ensure that the safety of a sunscreen product is not compromised by a particular combination of active and inactive ingredients," Michele explains.

She adds, "While we welcome comment on all of the draft guidances, we particularly encourage the public to comment on the approach to final formulation safety testing."

Given the variability of sunscreen products, and the fact that differences in sunscreen delivery vehicles can affect absorption and other safety factors, FDA expects that final orders on OTC sunscreen ingredients will include conditions requiring companies to conduct final formulation safety testing, just as they test final products to ensure compliance with recommended SPF levels and broad-spectrum protectiveness.

The agency says in vivo studies likely would not be required under conditions for marketing products containing monographed sunscreen ingredients. Instead, it expects that in vitro permeation testing of each new formulation would suffice, and companies would be advised to maintain records of such testing for FDA to access as needed.

FDA provides an overview of the permeation testing it foresees being a required condition for sunscreen marketers, which would involve testing products against a standard control formulation established by the agency for each sunscreen active ingredient and comparing their absorption rates using a human cadaver skin model.

The agency notes that it has not yet determined whether final formulation testing will be a requirement for individual sunscreen ingredients seeking GRASE status.

"FDA is particularly interested in comments that include a scientifically persuasive rationale as to why it is not necessary to conduct the anticipated final formulation safety testing for a particular sunscreen active ingredient, or that provide an alternative, scientifically supported approach to ensure that formulated sunscreen products containing that ingredient will have an acceptable safety margin," it says.

Regarding the draft guidance as a whole, Michele concludes: "As manufacturers review this guidance, we ask that they work on studies to address any safety data gaps for each of their sunscreen active ingredients being evaluated under the SIA. We also encourage sponsors to come in and talk to us so that we can address any questions they may have regarding these studies or the guidances."

FDA Drafts Guidance On Safety-Data Musts For GRASE Sunscreen Actives

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