Examining the monograph
Dissecting the FDA’s proposed rule on the over-the-counter sunscreen monograph and what dermatologists might expect in the coming years.
Feature
By Allison Evans, assistant managing editor, November 1, 2020
The U.S. Food and Drug Administration (FDA) has been regulating sunscreen since the beginning of the monograph system in 1972. In 1978, the first notice of proposed rulemaking for over-the-counter sunscreen drug products was published. At this time, cosmetic products with some therapeutic value were a fairly new concept, said Darrell S. Rigel, MD, past Academy president and member of the Academy’s Ad Hoc Task Force on Sunscreen. In the United States, UV filters and active ingredients of sunscreens are regulated as over-the-counter drugs, and as such, are subject to more intense regulation.
This month, DermWorld explores the FDA’s proposed rule on the over-the-counter (OTC) sunscreen monograph. Experts will shed light on the nearly 50-year process of OTC sunscreen rulemaking, the new testing and labeling requirements proposed in the rule, and the changes that have occurred since the proposed rule was published in early 2019.
A brief history of the sunscreen monograph
The history of the sunscreen monograph is a long and complicated one. To provide a capsule summary: After the initial 1978 proposal, a second tentative final monograph was issued in 1993, and a final monograph was published in 1999 — which was partially stayed in 2001 before it went into effect. In 2011, the FDA published yet another tentative final monograph, which, once again, was left dangling, Dr. Rigel said.
In May 2018, the FDA issued guidance stating that while the sunscreen monograph was stayed, FDA did not object to the marketing of sunscreens without an approved application if the sunscreens met certain standards outlined in the guidance.
2019 FDA proposed rule
In February 2019, the FDA released its most recent proposed rule for the OTC sunscreen final monograph, which addresses sunscreen active ingredients’ safety and dosage forms, sun protection factor (SPF), and broad-spectrum requirements. It also proposes updates on how products are labeled to make it easier for consumers to identify key product information.
Read a summary of the proposed rule and a list of safety questions below.
Highlights of the FDA’s 2019 proposed rule on OTC sunscreen products
Requests sunscreen manufacturers provide additional safety and effectiveness data on 12 sunscreen ingredients: oxybenzone, octinoxate, avobenzone, cinoxate, dioxybenzone, ensulizole, homosalate, meradimate, octisalate, octocrylene, padimate O, and sulisobenzone.
Proposes to raise the maximum proposed SPF value on sunscreen labels from SPF 50+ to SPF 60+.
Proposes to require sunscreens with an SPF value of 15 or higher to provide broad-spectrum protection. As SPF increases for broad-spectrum products, the extent of protection against UVA radiation should also increase.
Proposes that dosage forms that are generally recognized as safe and effective (GRASE) for use as sunscreens include sprays, oils, lotions, creams, gels, butters, pastes, ointments, and sticks.
Proposes that products that combine sunscreens with insect repellents are not GRASE.
Proposes that wipes, towelettes, body washes, shampoos, and other dosage forms be categorized as new drugs.
Proposes requiring the front of the sunscreen package to list the active ingredients.
Proposes to revise the formats for SPF, broad spectrum, and water resistance statements.
What safety data is the FDA requesting in the 2019 proposed rule?
Whether the ingredient causes skin irritation and/or allergic reaction when applied or when exposed to light.
The extent to which the ingredients are absorbed through the skin into the body.
Whether the ingredient would be considered generally safe and effective in children.
Whether the ingredient would cause tumors of the skin or rest of the body with long-term use.
Whether the ingredient would cause tumors systemically over long-term use.
Whether the ingredient would cause detrimental reproductive or hormonal effects over long-term use.
Whether the ingredient passes a toxicity test in animals to determine a safety margin for humans.
SPF cap
The 1999 monograph proposed a cap of SPF 30+ while the 2011 monograph suggested a cap of 50+. The 2019 proposal has increased the SPF cap to 60+. “There’s no science saying that there should be a cap one way or the other,” Dr. Rigel explained. “The argument for a cap is that the higher the number you get, the closer it is to 100% blocking — it asymptotically approaches 100%.”
The argument against the SPF cap, Dr. Rigel, explained, is that people under-apply sunscreen. All SPFs are tested at 2 mg/cm2 — and nobody applies that much, he stated. “People typically apply 25-50% of the rated amount, which means they typically get 25-50% of the rated SPF.” If the average sunscreen user applies SPF 100 sunscreen and applies 25% of the rated amount, they’re at least being protected with SPF 25, as opposed to the user who applies 25% of the SPF 60 and is, in reality, only being protected by SPF 15, Dr. Rigel explained.
The final argument against an SPF cap, said Dr. Rigel, is that companies are not going to get anything for developing higher and better protection sunscreens, so they won’t have the incentive to do the research to make better sunscreens.
Maximal use studies
The 2019 proposed rule includes provisions that industry conduct maximal use trials (MUsT) on UV filters that need more data for safety testing. A MUsT tests the active ingredients at the highest labeled dose that could be used in terms of amount, concentration, and surface area, said E. Dennis Bashaw, PharmD, senior science advisor to the director of the Office of Clinical Pharmacology at the FDA.
“There’s a whole list of ingredients being used in OTC drug products in which the vast majority of active ingredients have never actually been approved as drugs.”
─ David Fivenson, MD
“There’s a whole list of ingredients being used in OTC drug products in which the vast majority of active ingredients have never actually been approved as drugs,” said Michigan dermatologist David Fivenson, MD, a member of the Academy’s Climate Change and Environmental Affairs Expert Resource Group (ERG). The rule proposes these ingredients go through some degree of testing over time. “These ingredients are not quite grandfathered in, but industry is also not being told that they have to stop using them.”
A MUsT has been conducted for every approved topical dermatologic product approved under a New Drug Application (NDA) since the mid-1990s, Dr. Bashaw said. “For OTC topical products, the same MUsT paradigm provides important data linking human exposure to pre-clinical safety studies (animal studies).”
The FDA is proposing incorporating additional safety studies because public perception and real-world use of sunscreens has changed. “With one exception — ecamsule, which was approved via NDA for use in a few specific products — all current OTC sunscreens came to the U.S. market as part of proposals in the OTC Monograph, which has not been finalized. Also, since the monograph process started in the 1970s, attitudes regarding sun exposure in societal and clinical settings have changed,” Dr. Bashaw noted. SPF 15 was once referred to as “ultra” protection in the Federal Register, he said.
Without MUsT studies, it is impossible to know whether there are any health implications of using the UV filters, said Dr. Bashaw. “More studies are needed to determine if there are any carcinogenic, reproductive, or developmental effects.”
Dermal absorption
Before the 1990s, conventional wisdom was that topical products were not absorbed, or any absorption was considered insignificant, Dr. Bashaw said. “In the early 1990s, modern analytical methods showed that topically applied products do reach systemic circulation and can have biologic effects. What are the implications of this exposure for infants, adults, other demographics? We don’t know, but we need to look at it,” he said.
For the past 30 years or so, researchers have known that chemical (organic) sunscreen ingredients are systemically absorbed — there’s no question about it, said. Dr. Rigel. The public has been using sunscreens with the chemical ingredients in question since the late 1970s and early 1980s with no evidence of any toxic effects in humans, he said. The Academy echoed this in its comment letter to the FDA, stating that it “is not aware of any reports of serious adverse effects of sunscreen products, specifically any related to systemic absorption.”
“While it is probably safe, industry needs to do the studies to confirm,” said Henry W. Lim, MD, past Academy president and chair of the Academy’s Ad Hoc Task Force on Sunscreen. However, it should be emphasized that the fact that the FDA is asking for additional data does not mean sunscreen is not safe, he said.
FDA pilot studies
In May 2019, the FDA published the first of two pilot studies in JAMA (doi:10.1001/jama.2019.5586) to determine the maximum plasma concentration of four active ingredients (avobenzone, oxybenzone, octocrylene, and ecamsule) under maximal use conditions. Two mg/cm2 were applied (the amount used in FDA SPF testing) to 75% body surface area four times per day for four days. Plasma concentrations of greater than 0.5 ng/mL were reached for all UV filters after four applications on day one.
The FDA provided guidance that topically applied ingredients that resulted in plasma absorption greater than 0.5 ng/mL should undergo nonclinical toxicology assessment, including systemic carcinogenicity and additional developmental and reproductive studies. What is the significance of the 0.5 ng/mL threshold? According to Dr. Lim, that threshold is the standard used by the FDA for any type of study that measures percutaneous absorption. It’s not a threshold determined specifically for sunscreen ingredients.
“The study was done to be an exemplar to industry and to be a pilot to demonstrate how such a study could be done with sunscreens and to get an estimate as to the degree of absorption,” Dr. Bashaw stated. The studies were not designed to show risk or toxicity.
In a follow-up study published in January 2020 (doi:10.1001/jama.2019.20747), Matta et al assessed the systemic absorption and pharmacokinetics of six active ingredients (avobenzone, oxybenzone, octocrylene, homosalate, octisalate, and octinoxate) in four sunscreen products under maximal-use conditions. A randomized clinical trial was performed in 48 healthy people. Sunscreen was applied at 2 mg/cm2 to 75% body surface area at zero hours on day one, and four times on day two through day four at two-hour intervals.
The study found that all six of the active ingredients administered in four different sunscreen formulations were systemically absorbed and had plasma concentrations that surpassed the FDA threshold for sunscreen safety testing — and the threshold was surpassed after a single application.
These studies do not provide any evidence that chemical sunscreens cause harm. Importantly, the authors of the JAMA studies write, “These findings do not indicate that individuals should refrain from the use of sunscreen.”
What does the CARES Act have to do with sunscreen?
In 2014, the Sunscreen Innovation Act (SIA) was passed and signed into law. This legislation required the FDA to put into effect a final sunscreen monograph by Nov. 26, 2019, and established time frames for FDA’s review of sunscreen active ingredients not listed in the stayed 1999 final monograph.
“The SIA was intended to help expedite the process for sunscreen ingredient review and approval at the FDA. At the time, there were many sunscreen ingredient applications pending at the FDA — for over a decade — and the FDA had not approved a new ingredient in years,” said Christine O’Connor, the Academy’s associate director of congressional policy. These sunscreen ingredients, currently used around the world, have not been approved because the FDA did not have enough data to determine their safety and efficacy, she said.
The Coronavirus Aid, Relief, and Economic Stimulus (CARES) Act, enacted in March 2020, reformed the OTC monograph process. The legislation modernized the way OTC drugs are regulated in the United States, including changing the process the FDA uses to issue a generally recognized as safe and effective (GRASE) determination for additional active ingredients and ending the rulemaking process and transitioning to administrative orders, a more streamlined process, said James Scroggs, MHA, the Academy’s associate director of regulatory and payment policy. The CARES Act sunsets the SIA by the end of fiscal year 2022 — Sept. 30, 2022.
According to a July 2020 U.S. Government Accountability Office (GAO) report, administrative orders are expected to take less time to update and finalize requirements for OTC drugs, and using this new process could improve the FDA’s ability to address identified safety risks in a more timely and efficient manner.
As of June 2020, FDA officials informed the Academy that the agency has not yet completed its review of those provisions in the CARES Act that affect FDA’s regulation of OTC drugs, and therefore, could not comment on the specific requirements that will be included in the newly deemed administrative order, Scroggs explained.
“This incentivizes companies to create more innovative products and rewards a return on investment for new OTC drugs.”
─ Christine O’Connor, AADA associate director of congressional policy
Another notable change in the OTC drug reform is an 18-month exclusivity period if the drug’s active ingredient is new or if there has been a change in the conditions of use. “This incentivizes companies to create more innovative products and rewards a return on investment for new OTC drugs,” O’Connor said.
The CARES Act requires the FDA to issue a proposed administrative order to revise the sunscreen order no later than 18 months after enactment (by Sept. 27, 2021), with an effective date of at least one year after publication of the final administrative order.
How to talk to patients about sunscreen
Ingredient safety
One of the most immediate and potentially devastating responses to the FDA’s 2019 proposed rule on the OTC sunscreen monograph is public uncertainty and fear regarding the use of sunscreen. In addition to confusion and misperception caused by the proposed rule and the subsequent publications of the FDA studies on the “Effects of Sunscreen Application Under Maximal Use Conditions on Plasma Concentration of Sunscreen Active Ingredients,” some of the most commonly used sunscreen active ingredients like oxybenzone and avobenzone have been vilified for years, further entrenching public doubts about sunscreen ingredients.
For patients who are seriously concerned about using sunscreen, dermatologists can recommend mineral-based sunscreens. Dermatologists should explain to patients and the public that using broad-spectrum sunscreen with SPF> 30 is only one of the measures that can be used to reduce the deleterious effects of UV radiation; these include seeking shade, wearing hats, sunglasses, and protective clothing, and limiting outdoor activities during peak sunlight hours.
“If a patient is concerned about the safety of sunscreen, then use a mineral sunscreen containing titanium dioxide and zinc oxide,” said Henry W. Lim, MD, past Academy president and chair of the Academy’s Ad Hoc Task Force on Sunscreen. These ingredients, he added, are in the FDA’s Category I classification, which means the ingredient is generally recognized as safe and effective (GRASE) for the claimed therapeutic indication. Of the 16 UV filters listed in the FDA monograph, FDA proposed rule has categorized two as Category II (ingredients are not GRASE), while the remaining 12 are classified in Category III, which means there is insufficient safety data to make a positive GRASE determination.
As Warren R. Heymann, MD, wrote in an April 2020 issue of DermWorld Insights and Inquiries, “Focusing on sunscreens without consideration of other avoidance techniques is akin to relying on car airbags without concern for driving sober in a well-maintained automobile.”
Sunscreen and the environment
Over the last 10 years, there have been more studies to support the notion that chemical UV filters are negatively affecting our environment, said Dr. Lim, co-author of the 2019 JAAD article “Review of environmental effects of oxybenzone and other sunscreen active ingredients” (doi: https://doi.org/10.1016/j.jaad.2018.06.033).
“Oxybenzone has been associated with bleaching of coral reefs in laboratory settings. In nature, the reason for coral reef bleaching is multifactorial, with the warming of ocean water considered to be a major contributor,” Dr. Lim said. Oxybenzone has also been detected in water sources worldwide, as well as in fish.
“There’s been a very slow movement toward even acknowledging these potential environmental effects compared to Europe and very little impetus to bring other UV filters to the U.S. market compared to what’s available in Europe and Australia,” said Michigan dermatologist David Fivenson, MD, a member of the Academy’s Climate Change and Environmental Affairs Expert Resource Group (ERG).
The concern about the environmental impact of organic UV filters should not detract from educating the public on the importance of photoprotection, namely, to seek shade, wear photoprotective clothing when outdoors, and apply sunscreens on sun-exposed areas. This would allow people to protect their skin from the UV radiation and, at the same time, protect the environment, the JAAD review concluded.
Sunscreen for skin of color
Another question encountered by dermatologists is what types of sunscreens are best for darker-skinned individuals, Dr. Lim said. Most mineral products leave a ghostly white discoloration on the skin. “I recommend that patients try out a few tinted sunscreen products to find one that best matches their skin tone.”
“There are really fine micronized versions that may leave less of a chalky look,” said Texas dermatologist Adewole Adamson, MD, MPP, member of the Academy’s Skin Cancer and Skin of Color Workgroup, “but, the chemical sunscreens may be a more cosmetically acceptable option.”
Dr. Adamson takes a wholly evidence-based perspective regarding the use of sunscreen by people of color as a way to prevent melanoma. “We have not been able to clearly link UV exposure to melanoma in people who identify as nonwhite (Black, Hispanic, Asian). The relationship between melanoma and the sun is, at best, tenuous. Much of the epidemiologic data linking the sun to melanoma is in white people — studies conducted in Europe, Australia, or the United States that exclude people of color.”
In Black people, melanoma usually develops in parts of the body that receive less sun exposure, such as the palms of the hands and soles of the feet, Dr. Adamson said. “To be sure, Black people can get melanoma, but the risk is very low. For the average Black person, sunscreen is unlikely to reduce their low risk of melanoma any further. In the same way, men can develop breast cancer, however, we do not promote mammography as a strategy to fight breast cancer in men,” he explained.
Dr. Adamson acknowledges that sunscreen will aid in the prevention of wrinkling, photoaging, and freckling; however, better data need to be developed to determine whether there is a relationship between sunscreen use by people of color and melanoma, he said.
It’s Dr. Adamson’s hope that these uncertainties can be couched within the public health messaging, although he acknowledges the difficulties in attempting to build a tailored and nuanced public health message. “It’s much easier to say, ‘everybody’s the same and everyone should wear sunscreen.’ But you can’t do that if people’s risks are different.”
“If we could make these uncertainties clear to the public, it would engender trust that we have some humility around what we know and don’t know about UV, sunscreen, and people of color,” Dr. Adamson said.
What’s the status now?
The FDA and industry continue to work together on the safety testing methodology, said Scroggs. “The currently marketed sunscreen active ingredients can continue to remain on the market in the United States while safety testing is ongoing and while the FDA evaluates the comments it received in response to last year’s proposed rule,” he said. Those comments will influence what is in the proposed administrative order.
“Industry has often been critical of the requested testing because it’s expensive and time consuming,” said Dr. Lim. “But the two FDA dermal absorption studies show that it can be done.”
“The FDA has had very significant and frequent discussions with industry,” said Dr. Lim. “Industry has agreed to test 8 of the 12 category III UV filters because they feel the other 4 UV filters are not widely used.”
In the meantime, the National Academies will conduct its sunscreen review. While the review will be focused on the environmental aspect, Congress directed the Environmental Protection Agency (EPA) to contract with the National Academies for a review that included the effectiveness of sunscreen products in protecting the public health, Dr. Lim noted.
“Depending on the publication date of this report, it could influence the FDA’s proposed sunscreen order, which Congress states should be issued no later than Sept. 27, 2021,” Scroggs said. When the FDA does issue a final sunscreen order, industry will have at least a year to update its products available in the United States to conform with the final monograph.
“The biggest potential changes that may impact dermatologists are availability of sunscreen ingredients and the SPF cap,” Scroggs noted, “although we’re still a way off from any big changes.”
