Posted: 26 Feb 2019 06:41 PM PST
Back in 2014, The Sunscreen Innovation Act (“SIA”) amended the Federal Food, Drug, and Cosmetic Act with the goal of accelerating the review of sunscreen ingredients that had been proposed for addition to the sunscreen monograph. Although the original focus of the SIA was on ingredients that sought to be added via the time and extent application (“TEA”) process (see our blog post here), it also included a host of directives to FDA to issue guidances, certain procedural rules, and by November 26, 2019, a final rule on nonprescription sunscreens (the legislation did not include a deadline for a proposed rule). To date, FDA has met the deadlines for these various guidances and other actions (some are discussed here, here, and here). The only remaining significant item on the SIA “to-do” list is the final rule mandate.
On February 26, FDA issued the proposed rule which covers overall safety and effectiveness standards, and addresses the status of the active ingredients already covered by the stayed final rule (but not the TEA ingredients). Although safety of the various active ingredients is the main issue, the proposed rule also addresses a host of other issues, such as dosage forms, sun protection factor (“SPF”) limits and labeling requirements.
Safety
The core of the proposal focuses on safety. At the outset, FDA emphasizes that even though FDA concludes that the safety information for most of the active ingredients from the 1999 stayed monograph is insufficient to meet the standard for Generally Recognized as Safe and Effective (GRASE) Category I, and places the majority of active ingredients in Category III (insufficient evidence for safety), the Agency is not concluding that those sunscreen active ingredients are unsafe; the placement in Category III merely means that additional information is required in light of changed conditions – substantially increased usage and evolving understanding of skin cancer, and the contribution of various UV waves, as well as risks associated with topical products in general.
Since 1999, knowledge about safety for topical drug products for chronic use has evolved. FDA previously discussed the new safety requirements in the 2016 guidance issued pursuant to the SIA. FDA now considers topical safety issues, such as irritation, sensitization and photo-safety, bioavailability (systemic absorption) and adverse events, as well as carcinogenicity and reproductive toxicity when considering the safety of sunscreen products. The same standard applies for products marketed under a new drug application, or NDA, as well as for monograph products.
Based on the evaluation of available data, FDA concludes that titanium dioxide and zinc oxide (including their nanomaterial forms), are both mineral sunscreens that do not penetrate and are not absorbed through the skin. Thus, the safety evaluation does not need to consider more than direct effects on the skin. FDA has sufficient evidence that they are GRASE Category I. Based on existing data, FDA also has concluded that two active ingredients, amino benzoic and trolamine salicylate, are unsafe and, therefore, are Category II. Based on information available to FDA, these two active ingredients are not currently used in any sunscreens currently marketed in the United States.
For the remaining 12 active ingredients, cinoxate, dioxybenzone, ensulizole, homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate O, sulisobenzone, oxybenzone, and avobenzone, FDA has not identified safety concerns, but states that existing evidence suggests that these active ingredients are, or may be, absorbed through the skin, and data about the consequences of this absorption are missing. For each ingredient, FDA discusses the data available and identifies what additional studies are required. Although more data are available for oxybenzone and avobenzone than for the other 10 Category III ingredients, some data gaps exist.
FDA anticipates that it will require safety testing for final formulations of products containing active ingredients that are absorbed through the skin. Because, at this time, none of the Category I ingredients are absorbed, it does not propose such testing at this time.
FDA’s requirements regarding safety should not come as a surprise as they are consistent with the individual TEA orders it issued in 2014 and 2015, and with FDA’s 2016 guidance, as well as with the 2018 draft guidance describing recommendations for demonstrating absorption of topical OTC active ingredients for purposes of establishing GRASE status (the so-called “MUsT” guidance).
Dosage Forms
In an ANPR discussing dosage forms, FDA solicited information on spray sunscreens, and in the absence of evidence for the marketing of powder sunscreens before 1972, determined that this dosage form was not eligible for review. FDA has determined that sunscreens in the spray dosage form may be GRASE provided that the droplets size distribution meets certain requirements, and the label includes specific directions to minimize unintended inhalation and includes a flammability warning.
FDA received information to establish that sunscreen powders were marketed before 1972 and, therefore, are eligible for review. It requests further data on various issues such as whether the use of this dosage form should be limited to just the face.
Maximum SPF and Broad Spectrum Requirements
FDA discusses at some length new scientific information indicating the importance of broad spectrum protection to protect against UVA wavelength of 370 nm or higher. Based on this new information it proposes to amend the 2011 rule for sunscreen testing. Under the new proposal, all sunscreens labeled as SPF 15 or higher must be broad spectrum and must demonstrate protection against irradiation at wavelengths above 370 nm. These new requirements do not require a change in the testing method; all the required data can be calculated from information acquired by the current method.
FDA has tentatively determined that products with SPF 2-14 are not required to provide broad spectrum protection. Although such products provide no protection against skin cancer, they do reduce the risk of sunburn. FDA proposes to require prominent label statements to alert consumers to the limited benefit of these low SPF products. FDA also seeks comments on whether the limited benefits of low SPF sunscreens outweigh the risks (i.e., whether such products which protect only against sunburn are GRASE).
FDA also has reconsidered its position regarding the maximum SPF. It now proposes to set the maximum label SPF at 60+ and cap the actual SPF for such products at 80. Because SPF values vary, with increasing variability at higher values, FDA proposes that they be declared in increments of 5 for products with SPF 15-30, increments of 10 for products with SPF 30 to 60, and as 60+ for values in the range of 60-80.
Labeling Revisions
Although FDA’s labeling regulation for sunscreens was finalized only in 2011, the Agency proposes several changes, including a requirement to include on the principal display panel, the names of the active ingredients, a disclosure for products with SPF 2-14, and font size and color requirements for the statement of identity.
Efficacy Testing Final Formulation
Based on experience gathered in inspections and from other sources, FDA is concerned that testing for sunscreen formulations is not always conducted in a way that protects human subjects and produces reliable results. It proposes to amend the current regulation to clarify the requirements for an IRB and informed consent, use of qualified personnel to conduct the studies, and related requirements for clinical studies. Failure to observe these best practices will cause the product to be misbranded. Also, because final formulation testing constitutes the manufacture of a drug, failure to follow proper procedures in clinical tests for the sunscreen would result in an adulterated product. FDA also proposes specific record keeping requirements.
Sunscreen-Insect Repellant Products
FDA has (tentatively) determined that sunscreen-insect repellant products are not GRASE. FDA bases this determination primarily on the incompatibility of the intended uses and directions for use (sunscreen applied every 2 hours, insect repellant less frequently), and the lack of safety data about possible interaction.
Denial of Three Citizen Petitions
On the day that FDA announced the issuance of the proposed rule, it also responded to three Citizen Petitions related to sunscreen regulations. All three petitions were denied. Bare Escentuals Beauty, Inc. had requested that FDA recognize makeup powders as GRASE sunscreens. As mentioned above, FDA now recognizes powders as a possible dosage form, but FDA denied the petition because, at this time, the Agency has insufficient evidence that sunscreen powders are GRASE. In 2009, L’Oreal USA Product petitioned requesting that FDA amend FDA’s (stayed) regulation listing GRASE active ingredients to include 5% rather than 3% avobenzone. FDA denied this petition because, as discussed in the proposed rule, the Agency has insufficient evidence to conclude that avobenzone (at either percentage) is GRASE Category I. The third petition to which FDA responded was a Citizen Petition by Rapid Precision Testing Laboratories requesting that FDA determine that certain active ingredients included in the stayed monograph are not safe because of their alleged anti-inflammatory effects, thus inflating the SPF value of formulations containing the active ingredients, and that FDA amend the SPF testing method to avoid the alleged effect of anti-inflammatory substances. FDA concluded that there was insufficient evidence of the alleged effects and denied the Petition.
Effective Date
FDA proposes a comment period of 90 days and an effective date of November 26, 2019, for the final rule. This date undoubtedly is inspired by the date set in the SIA. This date would be optimistic in the best of circumstances; 6 months to analyze comments, and internal and administrative reviews, does not appear realistic. In addition, because of the host of data gaps for the Category III ingredients, we expect to see requests for deferral for many of these ingredients to allow time for collecting of additional data to demonstrate that they are GRASE. FDA proposes to allow ingredients deferred from the final rulemaking to remain on the market as the data are being generated.
Comments must be submitted by May 27, 2019.
On February 26, FDA issued the proposed rule which covers overall safety and effectiveness standards, and addresses the status of the active ingredients already covered by the stayed final rule (but not the TEA ingredients). Although safety of the various active ingredients is the main issue, the proposed rule also addresses a host of other issues, such as dosage forms, sun protection factor (“SPF”) limits and labeling requirements.
Safety
The core of the proposal focuses on safety. At the outset, FDA emphasizes that even though FDA concludes that the safety information for most of the active ingredients from the 1999 stayed monograph is insufficient to meet the standard for Generally Recognized as Safe and Effective (GRASE) Category I, and places the majority of active ingredients in Category III (insufficient evidence for safety), the Agency is not concluding that those sunscreen active ingredients are unsafe; the placement in Category III merely means that additional information is required in light of changed conditions – substantially increased usage and evolving understanding of skin cancer, and the contribution of various UV waves, as well as risks associated with topical products in general.
Since 1999, knowledge about safety for topical drug products for chronic use has evolved. FDA previously discussed the new safety requirements in the 2016 guidance issued pursuant to the SIA. FDA now considers topical safety issues, such as irritation, sensitization and photo-safety, bioavailability (systemic absorption) and adverse events, as well as carcinogenicity and reproductive toxicity when considering the safety of sunscreen products. The same standard applies for products marketed under a new drug application, or NDA, as well as for monograph products.
Based on the evaluation of available data, FDA concludes that titanium dioxide and zinc oxide (including their nanomaterial forms), are both mineral sunscreens that do not penetrate and are not absorbed through the skin. Thus, the safety evaluation does not need to consider more than direct effects on the skin. FDA has sufficient evidence that they are GRASE Category I. Based on existing data, FDA also has concluded that two active ingredients, amino benzoic and trolamine salicylate, are unsafe and, therefore, are Category II. Based on information available to FDA, these two active ingredients are not currently used in any sunscreens currently marketed in the United States.
For the remaining 12 active ingredients, cinoxate, dioxybenzone, ensulizole, homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate O, sulisobenzone, oxybenzone, and avobenzone, FDA has not identified safety concerns, but states that existing evidence suggests that these active ingredients are, or may be, absorbed through the skin, and data about the consequences of this absorption are missing. For each ingredient, FDA discusses the data available and identifies what additional studies are required. Although more data are available for oxybenzone and avobenzone than for the other 10 Category III ingredients, some data gaps exist.
FDA anticipates that it will require safety testing for final formulations of products containing active ingredients that are absorbed through the skin. Because, at this time, none of the Category I ingredients are absorbed, it does not propose such testing at this time.
FDA’s requirements regarding safety should not come as a surprise as they are consistent with the individual TEA orders it issued in 2014 and 2015, and with FDA’s 2016 guidance, as well as with the 2018 draft guidance describing recommendations for demonstrating absorption of topical OTC active ingredients for purposes of establishing GRASE status (the so-called “MUsT” guidance).
Dosage Forms
In an ANPR discussing dosage forms, FDA solicited information on spray sunscreens, and in the absence of evidence for the marketing of powder sunscreens before 1972, determined that this dosage form was not eligible for review. FDA has determined that sunscreens in the spray dosage form may be GRASE provided that the droplets size distribution meets certain requirements, and the label includes specific directions to minimize unintended inhalation and includes a flammability warning.
FDA received information to establish that sunscreen powders were marketed before 1972 and, therefore, are eligible for review. It requests further data on various issues such as whether the use of this dosage form should be limited to just the face.
Maximum SPF and Broad Spectrum Requirements
FDA discusses at some length new scientific information indicating the importance of broad spectrum protection to protect against UVA wavelength of 370 nm or higher. Based on this new information it proposes to amend the 2011 rule for sunscreen testing. Under the new proposal, all sunscreens labeled as SPF 15 or higher must be broad spectrum and must demonstrate protection against irradiation at wavelengths above 370 nm. These new requirements do not require a change in the testing method; all the required data can be calculated from information acquired by the current method.
FDA has tentatively determined that products with SPF 2-14 are not required to provide broad spectrum protection. Although such products provide no protection against skin cancer, they do reduce the risk of sunburn. FDA proposes to require prominent label statements to alert consumers to the limited benefit of these low SPF products. FDA also seeks comments on whether the limited benefits of low SPF sunscreens outweigh the risks (i.e., whether such products which protect only against sunburn are GRASE).
FDA also has reconsidered its position regarding the maximum SPF. It now proposes to set the maximum label SPF at 60+ and cap the actual SPF for such products at 80. Because SPF values vary, with increasing variability at higher values, FDA proposes that they be declared in increments of 5 for products with SPF 15-30, increments of 10 for products with SPF 30 to 60, and as 60+ for values in the range of 60-80.
Labeling Revisions
Although FDA’s labeling regulation for sunscreens was finalized only in 2011, the Agency proposes several changes, including a requirement to include on the principal display panel, the names of the active ingredients, a disclosure for products with SPF 2-14, and font size and color requirements for the statement of identity.
Efficacy Testing Final Formulation
Based on experience gathered in inspections and from other sources, FDA is concerned that testing for sunscreen formulations is not always conducted in a way that protects human subjects and produces reliable results. It proposes to amend the current regulation to clarify the requirements for an IRB and informed consent, use of qualified personnel to conduct the studies, and related requirements for clinical studies. Failure to observe these best practices will cause the product to be misbranded. Also, because final formulation testing constitutes the manufacture of a drug, failure to follow proper procedures in clinical tests for the sunscreen would result in an adulterated product. FDA also proposes specific record keeping requirements.
Sunscreen-Insect Repellant Products
FDA has (tentatively) determined that sunscreen-insect repellant products are not GRASE. FDA bases this determination primarily on the incompatibility of the intended uses and directions for use (sunscreen applied every 2 hours, insect repellant less frequently), and the lack of safety data about possible interaction.
Denial of Three Citizen Petitions
On the day that FDA announced the issuance of the proposed rule, it also responded to three Citizen Petitions related to sunscreen regulations. All three petitions were denied. Bare Escentuals Beauty, Inc. had requested that FDA recognize makeup powders as GRASE sunscreens. As mentioned above, FDA now recognizes powders as a possible dosage form, but FDA denied the petition because, at this time, the Agency has insufficient evidence that sunscreen powders are GRASE. In 2009, L’Oreal USA Product petitioned requesting that FDA amend FDA’s (stayed) regulation listing GRASE active ingredients to include 5% rather than 3% avobenzone. FDA denied this petition because, as discussed in the proposed rule, the Agency has insufficient evidence to conclude that avobenzone (at either percentage) is GRASE Category I. The third petition to which FDA responded was a Citizen Petition by Rapid Precision Testing Laboratories requesting that FDA determine that certain active ingredients included in the stayed monograph are not safe because of their alleged anti-inflammatory effects, thus inflating the SPF value of formulations containing the active ingredients, and that FDA amend the SPF testing method to avoid the alleged effect of anti-inflammatory substances. FDA concluded that there was insufficient evidence of the alleged effects and denied the Petition.
Effective Date
FDA proposes a comment period of 90 days and an effective date of November 26, 2019, for the final rule. This date undoubtedly is inspired by the date set in the SIA. This date would be optimistic in the best of circumstances; 6 months to analyze comments, and internal and administrative reviews, does not appear realistic. In addition, because of the host of data gaps for the Category III ingredients, we expect to see requests for deferral for many of these ingredients to allow time for collecting of additional data to demonstrate that they are GRASE. FDA proposes to allow ingredients deferred from the final rulemaking to remain on the market as the data are being generated.
Comments must be submitted by May 27, 2019.
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