In addition, there are data suggesting that combining some sunscreen active ingredients with the insecticide DEET may increase absorption of either or both components. Finally, we are proposing to lift the stay on the Final Monograph subject to the revisions to parts , , , and 21 CFR parts , [ 4 ] , , and described in this document , and have proposed revisions to these regulations necessary to effectuate the lifting of the stay and to harmonize any impacted regulations.
If finalized, the proposed rule would update and make effective regulations to ensure the safety and effectiveness of sunscreen products marketed under the OTC drug monograph. The rule would update sunscreen product labeling standards, address the safety of sunscreen active ingredients, revise and Start Printed Page clarify our expectations for testing and recordkeeping by entities that conduct sunscreen testing, and address other sunscreen safety or efficacy concerns, like combination sunscreen-insect repellents and alternative dosage forms.
Consumers would benefit from less exposure to sunscreen products containing active ingredients about which safety questions remain, less exposure to sunscreen products labeled with potentially misleading sun protection information, increased consumption of products with better UVA protection, less exposure to flammable spray sunscreens, and less exposure to spray and powder sunscreen products posing inhalation risks. Consumers would also experience transaction cost savings. The costs of the rule to sunscreen manufacturers include administrative costs, costs to fill data gaps for active ingredients and powder dosage forms, product formulation testing costs, and costs to reformulate and relabel sunscreen products.
Finally, testing entities would incur recordkeeping costs if they do not already maintain adequate records of testing equipment, methods, and observations in final formulation testing. In the following sections, we provide a brief description of terminology used in the OTC Drug Review regulations as well as an overview of OTC sunscreen products, their intended uses, and FDA's regulation of them.
OTC drug review. As described further below, the OTC Drug Review is generally conducted via a multiphase public rulemaking process each phase requiring a Federal Register publication , resulting in the establishment of a monograph for an OTC therapeutic drug category. Proposed, tentative final, and final monographs.
The proposed monograph, which is typically published in the form of an ANPR, is the end product of the first phase of the rulemaking process described above. An OTC drug may be legally marketed without an approved NDA or abbreviated new drug application ANDA if it meets each of the conditions contained in an applicable final monograph, the conditions contained in part , and any other applicable regulatory and statutory requirements for OTC drugs, including the labeling requirements in part As discussed in further detail in section IX.
Because SPF values represent a sunscreen's level of sunburn protection, they are primarily though not exclusively an indicator of expected protection from UVB radiation see section IX.
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Further, only products that have been demonstrated both to provide broad spectrum protection and to have a minimum SPF value of 15 have been shown to reduce the risk of skin cancer and early skin aging caused by the sun when used as directed with other sun protection measures. By contrast, sunscreens that have not been demonstrated to provide both broad spectrum protection and an SPF value of at least 15 have only been demonstrated to help prevent sunburn.
Our initial call for safety and efficacy data for sunscreen products was issued in 37 FR , December 12, FDA concluded that the above-listed ingredients at the listed concentrations could also be used in combination, with limited exceptions, provided that each active ingredient contributed a minimum SPF of 2 to the finished product 64 FR The effective date for complying with the Stayed Final Monograph was May 21, This deadline was extended 65 FR , June 8, and then stayed until further notice 66 FR , December 31, to provide additional time to resolve various outstanding issues, such as the labeling and testing of finished OTC sunscreen products.
This guidance was finalized in May Final Guidance Ref. Unless the failure to pursue regulatory action poses a potential health hazard to the consumer, FDA generally does not intend to object to the marketing of OTC sunscreen products that do not have an approved NDA or ANDA provided that they: 1 Contain as sunscreen active ingredients only the active ingredients or combinations of active ingredients listed in 21 CFR Major notices pertinent to today's proposed rule are summarized briefly in table 2 below:.
Eligibility for inclusion in an OTC monograph was originally limited to active ingredients and other conditions that had been used in drugs marketed in the United States prior to the inception of the OTC Drug Review in This proposed rule addresses the GRASE status and conditions of use applicable to sunscreen drug products containing active ingredients listed in the Stayed Final Monograph.
It does not address the pending sunscreen active ingredients that were originally submitted under the procedures established in the TEA regulation and are now being addressed through the SIA process. We are not revisiting the contribution that the active ingredients listed in the Stayed Final Monograph make to the effectiveness of sunscreens. The Agency has not received information suggesting that it is necessary to revisit its prior decision about the effectiveness of the active ingredients at this time. Consumer exposure to sunscreen active ingredients has increased dramatically since FDA began its initial safety evaluations of the sunscreen active ingredients at issue in this proposed rule.
Many factors have influenced this increase, including the following:. Relatively few sunscreen products were in use when the U. Army initially funded research into the development of effective sunscreen products for use by military personnel on aircraft carriers and others routinely exposed to long periods of intense sunlight during World War II Ref. The reach of sunscreen products began to broaden when they were later marketed for use specifically by consumers who sunburned readily i. Sunscreen products are now routinely used by a much broader range of consumers for protection against many types of sun-induced skin damage, not just sunburn.
Accumulating data demonstrate that increased sun exposure increases the risk of developing skin cancers and premature skin aging Ref. To help reduce the risk of these types of sun-induced skin damage, public health organizations including FDA have for years urged consumers to use sunscreen products along with other sun-protective behaviors like limiting time in the sun and wearing protective clothing Refs.
Another factor driving increased consumer exposure to sunscreen active ingredients has been the introduction and widespread adoption of sunscreen products with higher labeled SPF values. To achieve these higher SPFs, many currently marketed products are formulated with more active ingredients combined together in higher concentrations than were generally combined in products when FDA's review of OTC sunscreens began.
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Increased knowledge about the role of UVA radiation in causing skin damage has also encouraged the formulation of broad spectrum products with combinations of active ingredients designed to achieve protection against both UVA and UVB radiation. In addition, other widely used products, such as facial makeup, moisturizing creams, and lipsticks, have had sunscreen active ingredients added to their formulations.
These trends are reflected in the evolution of the current labeling provisions for sunscreen products regulated under the OTC monograph system. Changes in the instructions for using these sunscreen products have also contributed to increased use of, and exposure to, sunscreen active ingredients. The labeling recommended by the advisory panel in simply instructed consumers to apply sunscreen products liberally and to reapply after swimming or excess perspiration 43 FR at In recent years, a growing body of data has suggested that the transdermal absorption of some sunscreen active ingredients is greater than previously thought, and thus may raise previously unevaluated safety concerns, including the potential for reproductive, developmental, or carcinogenic effects.
As discussed in further detail in section VIII. This new information about absorption and potential safety risks is inadequate, by itself, to support an affirmative conclusion that products containing the active ingredients at issue are not safe.
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In light of these safety concerns, FDA held a meeting of its Nonprescription Drugs Advisory Committee NDAC on September 4 and 5, , to discuss the scope of safety testing that should be conducted to support general recognition of safety and effectiveness for active ingredients for use in nonprescription sunscreen products. FDA proposed the following safety testing paradigm:. Nonclinical toxicology data:. There was consensus among the committee members that FDA's proposed framework was a good starting point Ref. FDA finalized this guidance in November , after considering public comment on its draft recommendations Ref.
All sunscreens marketed without an NDA are subject to the same standard: General recognition of safety and effectiveness. Accordingly, as noted previously, the data that we expect to be necessary to evaluate the safety and effectiveness of the sunscreen monograph active ingredients are the same as those we recommended as necessary to evaluate the safety and effectiveness of sunscreen active ingredients previously considered under the procedures established in the TEA regulation and now being considered pursuant to the framework established by the SIA see Safety and Effectiveness Data Guidance Ref.
The studies described in this section are generally needed for FDA to determine that a sunscreen active ingredient is GRASE for use in nonprescription sunscreens. Specific data gaps for individual active ingredients depend on the quality and quantity of available safety data, and are identified in section VIII. As described in that section, those active ingredients for which the existing public record contains sufficient data to support a positive GRASE finding are proposed as Category I.
Those for which additional data are necessary are proposed as Category III. In addition, in evaluating the existing safety data for the active ingredients listed in the Stayed Final Monograph, FDA determined that the risks associated with two of these ingredients outweigh their benefits. FDA recognizes the contribution that broad spectrum sunscreens with an SPF value of 15 or higher can make to decreasing the risk of skin cancer and early skin aging caused by the sun if used as directed with other sun protection measures.
To protect the public health, however, it is also important for FDA to balance the potential benefits of these sunscreen products to consumers against their potential risks. Providing an adequate safety margin for OTC sunscreen active ingredients and finished sunscreen products is a key element of FDA's risk assessment. A safety margin calculation takes the highest animal NOAEL and estimates a maximum safe level of exposure for humans.
Because animal studies do not always predict effects in humans, the actual threshold for an effect in humans may be different i.
The human sensitivity to a drug is often unknown. To account for this, the predicted safe exposure level in humans that is reflected in the safety margin is well below where toxicities were seen in animals. In determining the specific testing and other data needed to adequately demonstrate that an OTC sunscreen active ingredient is safe, FDA considers both the circumstances under which OTC sunscreen products are intended to be used by consumers i. FDA's approach to the clinical safety evaluation of OTC sunscreen active ingredients is based on our current scientific understanding regarding safety evaluation of topical drug products for chronic use, and thus is generally consistent with the safety data requirements that would apply to an NDA for a chronic-use topical drug product i.
FDA's approach to the nonclinical safety evaluation of these active ingredients takes into account their lengthy marketing history in the United States. In contrast to nonclinical data requirements for a chronic-use topical drug product NDA, which include results from comprehensive nonclinical pharmacology and toxicology safety testing, the approach to nonclinical safety testing in this proposed rule is largely focused on potential long-term adverse effects or effects not otherwise readily detected from human use i.
Additional testing beyond what is described below may be recommended for active ingredients for which data suggest a concern about other long-term effects, such as hormonal disruption. In addition, although sunscreen products are typically formulated with two or more active ingredients, the framework described below contemplates that testing will be performed using formulations that include one active ingredient.
Generally, unless data suggest that there may be a safety or efficacy concern with a particular combination of active ingredients, we anticipate that an active ingredient that is found to be GRASE for use in sunscreens could be combined with other active ingredients that are also GRASE for use in sunscreens. If data suggest that there may be a safety or efficacy concern with a particular combination of active ingredients or active and inactive ingredients , additional data may be necessary to support a positive GRASE determination for sunscreens containing that combination.
The following sections describe the specific safety data that FDA expects the Agency will need to determine whether an active ingredient is GRASE for use in sunscreens. Human dermal safety studies for topical products in which exposure to light after application is anticipated generally consist of two sets of studies—those conducted without specific exposure to light and those conducted to assess reactions after UV exposure photosafety studies Ref.
The studies usually consist of dermal irritation patch testing, dermal sensitization patch testing, dermal phototoxicity testing, and dermal photoallergenicity testing. Because marketed sunscreen products typically contain a combination of active ingredients, and product formulations frequently change, it is difficult to determine causal links between individual active ingredients and reported irritation and hypersensitivity adverse events associated with a particular product.
Therefore, FDA generally expects to use data from human dermal irritation studies, human dermal sensitization studies, and human dermal photosafety studies, in conjunction with postmarketing adverse event data, to inform GRASE determinations and labeling. For example, if FDA concludes that there is a positive risk-benefit profile for a sunscreen active ingredient, but that it is known to be a sensitizer, it may be possible to develop safety labeling to address this risk without data generated in the human dermal safety studies described below see, e.
Human dermal irritation and sensitization studies. Studies of dermal irritation and sensitization, using the repeat insult patch test or other relevant tests, are elements in the safety evaluation of topical drug products that, like sunscreens, are applied to the skin repeatedly over long periods of time. In dermal irritation studies, a test substance is applied to a small pad patch and affixed to the test subject's skin, usually on the back, to determine whether the ingredient causes direct skin toxicity.
Dermal sensitization studies are conducted similarly but are designed to detect immunologically mediated reactions, which require prior exposure to the allergen.