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SCHERING-PLOUGH PROPOSES APP IN VITRO UVA TESTING METHODOLOGY

This article was originally published in The Tan Sheet

Executive Summary

SCHERING-PLOUGH PROPOSES APP IN VITRO UVA TESTING METHODOLOGY to FDA in Nov. 1 comments on the sunscreen tentative final monograph. Schering's method for determining a sunscreen's APP, or UVA protection percentage, relies on numerical calculations based on the Commission Internationale de L'Eclairage (CIE) hazard spectrum and values derived from SPF testing. Schering-Plough said it favored the "adoption of an in vitro test method for determination of UVA protection for normal skin which does not rely on either photosensitizers or non-solar UVA light sources." The TFM was published on May 12 ("The Tan Sheet" May 17, pp. 10- 19). Schering-Plough's comments expand upon earlier presentations to FDA on the APP system in May 1988 and April 1990. An APP designation was also used on labeling for the company's Shade sunscreen in 1990. However, Schering-Plough subsequently removed the designation from the product and pledged to work further on the method when FDA stated in an Oct. 5, 1990 regulatory letter that the UVA-protection claim was "false and misleading" since it had not been officially approved. At that time, the agency threatened industry-wide action against any firms making UVA claims. Under Schering's proposed method, UVA protection would be calculated by first determining the UV absorbance spectrum of a sunscreen product. A "convolution spectrum" would be calculated "by multiplying the solar spectrum with the CIE hazard spectrum," the company explained. The sunscreen transmission spectrum would then be incorporated into the convolution spectrum "to obtain a UVA effectiveness ratio," which, Schering noted, would be expressed as the UVA protection percentage. This APP, the company said, "represents the fraction of full spectrum UVA (320-400 nm) removed by a product." The most important advantage of using the APP method, Schering maintained, is that it "was conceived, designed and developed to be a subset of the existing SPF for sunscreen drug products" and, therefore, "it relates to an erythemal endpoint for normal skin." In addition, Schering-Plough said the APP method "does not unnecessarily duplicate clinical testing" because it uses values derived from required SPF testing. "Finally," Schering declared, the APP method "clearly demonstrates whether a sunscreen product provides meaningful protection against UVA radiation and is extremely useful in determining the comparative UVA protection of sunscreens." The "only variable" in the APP method, according to Schering- Plough, "is the spectrum unique to each product," since the APP is based on both normal erythemic risk and standard sunlight. Because "the original full spectrum (290-400 nm) method also produces an SPF value analogous to the SPF clinically determined according to FDA guidelines," the company explained, "APP has direct relevance to the SPF determined on human subjects and is a subset of the full spectrum SPF determination specific to UVA." The company noted that "it is simple to take the full spectrum (290-400 nm) absorbance spectrum and calculate the APP" based on the clinically determined SPF. Schering-Plough recommended that an APP of 50% "be used as the threshold definition of 'meaningful' UVA protection," which would correlate with FDA's proposal to require a minimum SPF 2 before sunscreen claims can be made for a product. Schering-Plough's comments question the suitability of other UVA testing methods that use photosensitized subjects, modified lamps on unsensitized subjects, or base results on immediate pigment darkening (IPD) endpoints. The company suggested that using photosensitizers, such as anthracene or 8-methoxypsoralen, is the "least desirable" testing method because of the potential carcinogenicity associated with photosensitizing agents and the absence of data demonstrating that test results relate "to product performance on normal skin." Regarding EPD testing, Schering "strongly" urged FDA not to adopt such methods for testing UVA protection that have "no correlation to erythema or other recognized endpoint of biological damage." Schering-Plough argued that IPD, a brownish-gray photochemical change in the skin's melanin caused by long-wave UVA and other visible fight, "has not been demonstrated to be a direct or surrogate endpoint for biological damage." The company maintained that "the action spectrum for IPD does not track the CIE spectra for known skin damage from sunlight UVA" and, therefore, "there is no relationship between a product's ability to prevent IPD and to prevent skin damage from sunlight." Schering said it looked "very carefully and extensively" at UVA study methods using modified lamps to deliver full spectrum UVA (320-400 nm) to non-photosensitized test subjects but rejected the model because it "inappropriately removes too much of the damaging" short-wave UVA rays. Consequently, Schering maintained, the UVA efficacy for some products is overestimated and for others underestimated. Johnson & Johnson, in separate Nov. 4 comments that raised objections similar to Schering's, also rejected IPD and photosensitization as appropriate UVA testing methods. In addition, J&J noted that it "ideally . . . would like to support an in vitro test methodology" due to the "inherent difficulties involved in in vivo UVA testing methods." However, J&J added that, "as a matter of priority, we feel that a validated in vivo human UVA test method must first be established against which future in vitro test methods can be tested and validated." J&J said it has been "active in developing" an in vivo UVA test method "for several years" that uses a modified lamp that "virtually" eliminates UVB radiation. J&J's method, in a study to be published in an upcoming Journal of the American Academy of Dermatology, "was capable of distinguishing three levels of UVA protection in sunscreens containing 0, 2, and 5% oxybenzone." In addition, J&J noted, its method was "incapable of distinguishing" between placebo and strong UVB absorber padimate-O, "indicating that [the test] method is not influenced by the presence of a strong UVB blocker in the formulation." J&J maintained that its method evaluates erythema and only erythema caused by UVA radiation. In addition, both J&J and Schering were critical of FDA's opinion that high SPF factor sunscreens may pose an increased risk of UVA radiation exposure. Both companies maintained that an SPF above 15 cannot be achieved without significant absorption in the short-wave UVA range. Schering also argued that FDA "overstated the case on comparative risks between UVB and UVA rays." Commenting in support of the IPD test method were a number of companies, including Procter & Gamble, L'Oreal and Cosmair. L'Oreal urged FDA to "immediately accept" the IPD testing method for UVA protection in a Nov. 4 letter to OTC Monograph Review Staff Director William Gilbertson. P&G cited an eight-center study sponsored by the Cosmetic, Toiletry and Fragrance Association in support of its contention that the IPD procedure "can reliably discriminate among products that provide meaningful long wavelength UVA protection." P&G also criticized Schering's proposed APP methodology and J&J's proposed PFA test, contending that the two methodologies can overestimate UVA protection. Regarding the APP test, P&G asserted that the "nature" of the test "is difficult to extend to a human in vivo situation and does not have utility in studying substantivity or stability." P&G suggested that the PFA test "for the most part" ignores the contribution of longer UVA wavelengths.
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