Filling in the Evidence About Sunscreen Robert M

Opinion

EDITORIAL

Filling in the Evidence About Sunscreen Robert M. Califf, MD; Kanade Shinkai, MD, PhD

Skin cancer is the most common malignancy in the United through day 7 for all products except the cream. The concen- States and is estimated to affect more than 3.3 million indi- tration increased from day 1 to day 4, raising the suggestion viduals each year.1 Photoprotection, including sunscreen use of drug accumulation. Application of products with oxyben- for areas of skin not covered zone and octocrylene resulted in similar exposures, with by sun protective clothing or concentrations exceeding 0.5 ng/mL, demonstrating rising Related article shade, aims to reduce expo- plasma concentrations with ongoing use—consistent with sure to UV radiation, likely drug accumulation—as well as persistent systemic levels the main risk factor for the development of skin cancer. after discontinuing the sunscreen use, suggesting an Sunscreens were initially approved as over-the-counter extended half-life. Among the 6 participants using the cream (OTC) medications—indicated for the prevention of sunburn— (the only product with ecamsule), 5 had ecamsule concen- before the modern era of drug evaluation. Current understand- trations exceeding 0.5 ng/mL on day 1. Notably, post hoc ing of UV-related carcinogenesis supports the additional analysis demonstrated that almost all study participants had indication regarding use of sunscreen for the prevention of systemic levels exceeding the FDA threshold after a single skin cancer. However, because biological rationale has so day of sunscreen application. often proven to be misleading, drug manufacturers must dem- The demonstration of systemic absorption well above onstrate through empirical research in humans that benefits the FDA guideline does not mean these ingredients are outweigh risks for an intended use of a product in a specified unsafe. However, the study findings raise many important population. Has sunscreen met these current requirements questions about sunscreen and the process by which the for safety and effectiveness? sunscreen industry, clinicians, specialty organizations, and Concerns have been raised about the safety and effects of regulatory agencies evaluate the benefits and risks of this chemical sunscreens on endocrine, reproductive, develop- topical OTC medication. First and foremost, it is essential to mental, and cancer-related outcomes, as well as environmen- determine whether systemic absorption of sunscreen poses tal harm.2,3 Evidence that sunscreen may be systemically risks to human health. Second, the effects of different sun- absorbed was indicated by studies in humans as early screen formulations, clinical characteristics (ie, skin type, as 19974; in 2008, the Centers for Disease Control and Preven- age, presence of skin diseases that disrupt the skin barrier), tion demonstrated the presence of the common sunscreen physical activity level, and exposure to sun and water on ingredient oxybenzone in 97% of urine samples collected as systemic sunscreen levels require further study. An urgent part of the National Health and Nutrition Examination Survey.5 question involves absorption in infants and children, who However, there is a paucity of careful and systematic study have different ratios of body surface area to overall size and of a fundamental aspect of drug development: measurement whose skin may absorb substances at differential rates. of blood levels of active sunscreen ingredients over time when Understanding whether systemic levels result from means the product is used as directed. other than transdermal absorption, such as through inhala- The study by Matta et al6 in this issue of JAMA reports tion of spray sunscreen formulations, or from other sources findings from an open-label, randomized, 4-group pilot of these chemicals, including cosmetic products and indus- study in 24 adults to determine the systemic absorption and trial sources, also warrants clarification. In addition, testing pharmacokinetics of the sunscreen ingredients avobenzone, under actual use conditions will be paramount, as most oxybenzone, octocrylene, and ecamsule during maximum users apply less sunscreen than the recommended amount, sunscreen use. The study protocol required application often without reapplication.8 Although applying less sun- (2 mg/cm2) 4 times a day to 75% of body surface area for screen theoretically reduces safety concerns, whether 4 days. Each intervention group received a different combi- a lower dose also diminishes the putative benefits of nation of active sunscreen ingredients within commercially sunscreen is not known. available cream, lotion, or spray formulations. The sunscreen ingredients examined by Matta et al are The authors found evidence of measurable systemic found in the most commonly accessible formulations avail- absorption of all 4 sunscreen ingredients at levels meeting able in the United States and were applied at recommended the US Food and Drug Administration (FDA) guidelines to amounts and intervals consistent with current sunscreen trigger a requirement for further systemic safety testing.7 labeling. Sunscreen users reasonably presume that compa- Specifically, all 4 sunscreen products containing avobenzone nies that manufacture and sell sunscreens have conducted resulted in plasma concentrations above 0.5 ng/mL. These basic studies to support the safety and effectiveness of their levels were evident on day 1 with all products and lasted products and that the medical profession would demand

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high-quality evidence. However, sunscreens have not been removal of sunscreen formulations containing these subjected to standard drug safety testing, and clinicians and ingredients from the US market. However, these deadlines consumers lack data on systemic drug levels despite decades can be extended if manufacturers commit to undertake the of widespread use. Furthermore, appropriately designed needed studies. trials have not yet been conducted to understand the opti- New sunscreen UV filters will require similar systemic mal sunscreen dose needed to achieve a balance of risk and safety studies, if these agents are significantly absorbed. benefit when used to prevent skin cancer and melanoma. Many sunscreen ingredients requiring additional testing The paucity of pharmacologic and clinical outcome evi- (and some awaiting approval) are critical to broad-spectrum dence is multifactorial. Despite multiple efforts by the FDA formulations—providing protection from UVA1 light in to persuade sunscreen manufacturers to conduct key safety particular—another requirement under the FDA monograph. studies, the manufacturers have failed to produce such data, Mineral sunscreens are less effective at meeting this forcing the FDA to conduct its own studies.9 In 2014, a pub- requirement unless used at high concentrations, which lic advisory panel convened by the FDA concluded that often results in cosmetically noticeable whitening of insufficient evidence existed to confirm the safety of many the skin. sunscreen ingredients and formulations.10 The panel also The findings of the study by Matta et al will likely raise concluded that high-quality evidence existed to demon- concerns in the medical community, as well as among strate prevention of sunburn, precancerous actinic keratosis, sunscreen users. Until more information is available, it and squamous cell cancer through sunscreen use but that will be important to continue to reinforce clinical evidence for melanoma prevention was not high quality. The recommendations15 regarding the beneficial effects of panel recommended specific information to allow older sun- photoprotection for skin cancer prevention that are rooted screen ingredients to remain on the market or to permit new in strong biological rationale and modest clinical evidence. ingredients to be marketed. The need for long-term safety Avoidance of the sunscreen ingredients highlighted in this data, as well as the challenges of performing effectiveness study, or of sunscreen altogether, could have significant studies on a population level, were acknowledged. negative health implications. At a minimum, physicians Delay in generating high-quality evidence is also rooted should recommend use of sunscreen formulations contain- in the regulatory history of sunscreen.11,12 Although regu- ing GRASE ingredients such as titanium dioxide and zinc lated as cosmetics throughout much of the world, sun- oxide as part of a larger program of photoprotection that screens in the United States have been subject to the FDA includes seeking shade, and wearing protective clothing, monograph system that evaluates OTC drug safety and effec- hats, and sunglasses, until meaningful answers to these tiveness. Multiple efforts to modernize this iterative system questions are available. to enable more rapid incorporation of evidence-based Understanding the effectiveness and safety of sunscreen changes have been unsuccessful. In 2014, Congress passed the ingredients will require a collaborative effort by industry, cli- Sunscreen Innovation Act to expedite entry of sunscreens nicians, and scientists. The power of collaboration is exem- available worldwide to the United States through an alterna- plified by the significant influence of the pharmaceutical tive FDA process while maintaining standards of drug evalu- industry, patient advocacy, regulatory modernization, and ation. Additionally, a 2019 proposed rule will finalize a sun- professional effort by dermatologists, surgeons, and oncolo- screen monograph, first issued in 1999, later this year.13,14 This gists in the recent development of highly effective therapies rule proposes “generally regarded as safe and effective” for patients diagnosed with melanoma. A similar collabora- (GRASE) designation for 2 mineral sunscreens (zinc oxide and tive effort is needed with regard to sunscreen, because pre- titanium dioxide) and designation of 2 others (para- venting skin cancer is superior to treating it after diagnosis. aminobenzoic acid [PABA]; trolamine salicylate for use as sun- The FDA monograph process should also be reformed into screen) as not GRASE. Twelve additional ingredients (includ- an efficient, systematic process that ensures routine safety ing avobenzone, oxybenzone, and octocrylene—3 of the 4 testing, generation of high-quality evidence of benefit, and sunscreens examined in the study by Matta et al) will receive improved labeling for OTC medications in a manner that pre- “insufficient evidence” of GRASE, requiring additional test- serves FDA autonomy in judging the balance of benefit and ing. Failure to provide standard safety data, which includes risk for intended uses of drugs. Industry and the biomedical evaluation for systemic absorption—and, if positive— community should partner to develop sunscreens with systemic carcinogenicity and reproductive impact studies, minimal systemic absorption that are proven to prevent by the November 2019 deadline could in theory result in the skin cancer and melanoma.

ARTICLE INFORMATION Corresponding Author: Kanade Shinkai, MD, PhD, Conflict of Interest Disclosures: Dr Califf reported Author Affiliations: Duke Forge, Duke University Department of Dermatology, University of serving on the corporate board for Cytokinetics and School of Medicine, Durham, North Carolina California, San Francisco, 1701 Divisadero St, as the board chair for the People-Centered (Califf); Verily Life Sciences (Alphabet), South San Third Floor, San Francisco, CA 94115 Research Foundation and receiving consulting fees Francisco, California (Califf); Department of ([email protected]). from Merck, Biogen, Genentech, Eli Lilly, and Dermatology, University of California, San Francisco Published Online: May6,2019. Boehringer Ingelheim. Dr Shinkai reported no (Shinkai); Editor in Chief, JAMA Dermatology doi:10.1001/jama.2019.5528 disclosures. (Shinkai). Additional Information: Dr Shinkai is a voting member of the American Academy of Dermatology

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(AAD) regulatory policy committee. Dr Califf was 5. Calafat AM, Wong L-Y, Ye X, Reidy JA, Needham 10. US Food and Drug Adminisration (FDA). the Commissioner of Food and Drugs for the US LL. Concentrations of the sunscreen agent Summary Minutes of the Nonprescription Drugs Food and Drug Administration from February 2016 benzophenone-3 in residents of the United States: Advisory Committee (NDAC) Meeting, September to January 2017 and Deputy Commissioner for National Health and Nutrition Examination Survey 4-5, 2014. FDA website. https://wayback.archive-it. Medical Products and Tobacco for the US Food 2003-2004. Environ Health Perspect. 2008;116(7): org/7993/20170404152726/https://www.fda.gov/ and Drug Administration from February 2015 to 893-897. doi:10.1289/ehp.11269 downloads/AdvisoryCommittees/ January 2016. 6. Matta MK, Zusterzeel R, Pilli NR, et al. Effect of CommitteesMeetingMaterials/Drugs/ Disclaimer: The views expressed represent those sunscreen application under maximal use NonprescriptionDrugsAdvisoryCommittee/ of the authors and do not necessarily represent the conditions on plasma concentration of sunscreen UCM421304.pdf. 2014. Accessed May 1, 2019. views of the affiliated organizations. active ingredients: a randomized clinical trial 11. Sharfstein JM. A spotlight on sunscreen [published online May 6, 2019]. JAMA. doi:10.1001/ regulation. N Engl J Med. 2015;373(2):101-103. doi: REFERENCES jama.2019.5586 10.1056/NEJMp1504912 1. American Cancer Society (ACS). Cancer Facts & 7. US Food and Drug Administration (FDA). 12. Califf RM, Ostroff S. Sunscreen and the FDA. Figures 2019. ACS website. https://www.cancer. Nonprescription sunscreen drug products—safety N Engl J Med. 2015;373(2):197. doi:10.1056/ org/content/dam/cancer-org/research/cancer- and effectiveness data. FDA website. NEJMc1507737 facts-and-statistics/annual-cancer-facts-and- https://www.fda.gov/regulatory-information/ 13. US Food and Drug Administration. Sunscreen figures/2019/cancer-facts-and-figures-2019.pdf. search-fda-guidance-documents/nonprescription- drug products for over-the-counter human use: Published 2019. Accessed April 6, 2019. sunscreen-drug-products-safety-and- proposed rule. Federal Register website. effectiveness-data. August 2018. Accessed May 1, https://www.federalregister.gov/documents/2019/ 2. Schneider SL, Lim HW. Review of environmental 2019. effects of oxybenzone and other sunscreen active 02/26/2019-03019/sunscreen-drug-products-for- ingredients. J Am Acad Dermatol. 2019;80(1):266- 8. Petersen B, Wulf HC. Application of over-the-counter-human-use. February 2019. 271. doi:10.1016/j.jaad.2018.06.033 sunscreen—theory and reality. Photodermatol Accessed April 25, 2019. Photoimmunol Photomed. 2014;30(2-3):96-101. 14. Food and Drug Administration, HHS. Sunscreen 3. Yeager DG, Lim HW. What’s new in doi:10.1111/phpp.12099 photoprotection: a review of new concepts and drug products for over-the-counter human use: controversies. Dermatol Clin. 2019;37(2):149-157. 9. US Food and Drug Administration (FDA). From final monograph. Fed Regist. 1999;64(98):27666- doi:10.1016/j.det.2018.11.003 our perspective: helping to ensure the safety and 27693. effectiveness of sunscreens. FDA website. 4. Hayden CGJ, Roberts MS, Benson HA. Systemic 15. American Academy of Dermatology (AAD). https://www.fda.gov/drugs/news-events-human- Sunscreen FAQs. AAD website. https://www.aad. absorption of sunscreen after topical application. drugs/our-perspective-helping-ensure-safety-and- Lancet. 1997;350(9081):863-864. doi:10.1016/ org/media/stats/prevention-and-care/sunscreen- effectiveness-sunscreens. November 2016. faqs. 2018. Accessed April 6, 2019. S0140-6736(05)62032-6 Accessed April 25, 2019.

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