FDA's denial of the two remaining sunscreen time-and-extent applications, including one for an ingredient available OTC through a new drug application process, signals “nothing's going to get to market” anytime soon through monograph changes, says an advisor for an advocacy group.

The agency, meanwhile, says legislation Congress passed in 2014 to facilitate making more sunscreen ingredients available did not lower the threshold for adding ingredients to the OTC monograph – generally regarded as safe and effective.

In separate proposed orders in the Feb. 25 Federal Register, FDA rejects [L'Oreal USA Inc.]'s TEA for ecamsule, already used in multiple OTC sunscreens marketed by the firm through a 2006 NDA approval, and Merck & Co. Inc.'s TEA for enzacamene. FDA says each firm can submit additional information to support its proposal.

In each order, FDA's Center for Drug Evaluation and Research says the ingredient “is not generally recognized as safe and effective...and is misbranded when used in [OTC] sunscreen products because the currently available data are insufficient to classify it as GRASE and not misbranded, and additional information is needed to allow us to determine otherwise.”

The 2014 Sunscreen Innovation Act established deadlines for FDA review of sunscreen TEAs, which seek GRASE status for active ingredients on the basis of safety and efficacy data from products marketing in countries outside the U.S.

The notices for ecamsule and enzacamene follow FDA’s publication in January of proposed orders on its decisions to deny six other sunscreen ingredient TEAs, the agency’s first action compelled by SIA. The act also required FDA to publish the proposed orders on its decisions for the remaining TEAs by Feb. 24 ([A#05150112007]).

In a same-day statement on FDA’s website, CDER Division of Nonprescription Clinical Evaluation Director Theresa Michele said the agency realizes its sunscreen TEA decisions “may be disappointing to some who would like to see additional sunscreen products on the market immediately.”

However, SIA did “not change FDA’s standard for” GRASE, though the act “requires strict deadlines for FDA to take action on these ingredients,” Michele said.

Moreover, the law does not provide FDA with additional resources to evaluate TEAs nor guarantee that products with additional sunscreen ingredients will be on the market in a specified timeframe, she said.

Marketing history on ingredients long available in other countries “doesn’t tell us anything about the long-term effects from use” of an ingredient or how much of it is absorbed, Michele added, noting “apparent confusion as to why” some ingredients are not approved in the U.S.

Comments on the proposed orders are due within 45 days of publication in the Federal Register.

Moving The Goal Post?

The orders are a major blow to stakeholders, including the Public Access to Sunscreens coalition. The group’s policy advisor, Michael Werner, suggests FDA's approach is undermining the entire point of the SIA.

“This means that they've rejected all applications pending, which have been pending for a long time,” said Werner, a partner at law firm Holland & Knight.

“This is inconsistent with the Surgeon General’s call to action on skin cancer, where he said the government needs to take proactive steps to do something about rising rates of skin cancer. This is even inconsistent with FDA's own process,” he added in an interview.

“We want to collaborate with, and work with FDA, and there has to be something everyone feels good about it. But the frustration you have here is that the goal post has moved,” Werner said.

He said the denial of the ecamsule TEA underscores the agency's reluctance to work outside the NDA process. He pointed out ecamsule was approved in an NDA in 2006 Also see "L’Oréal’s Anthelios SX Will Launch Following FDA Approval Of UVA Filter" - Pink Sheet, 31 July, 2006..

However, the ingredient also was “languishing” under the TEA review process for sunscreen in the same period, only to be rejected in the end, Werner said.

“Here, L'Oreal can market that product under its new drug application, but it's not allowed to market it through the TEA process. It's a mystery,” he said.

“Like the other products FDA has not approved under the TEA process, the agency's message today is that manufacturers must submit data through a process with requirements that mimic the NDA process. This is not tenable for sunscreen and will result in delayed access to new products for Americans.”

FDA officials have noted a higher bar for reviews of TEA applications than for NDAs. At a public meeting Feb. 4, Office of New Drugs Director John Jenkins said the TEA process is an “arguably higher standard” ([A#05150223008]).

The NDA process is product-specific, allowing marketing of only those products approved to contain a certain ingredient. Monographs, however, cover multiple ingredients across an intended-use category – those ingredients can be used in any appropriate product by any firm complaint with FDA manufacturing regulations.

However, while monograph OTCs do not need premarket approval before launch, adding an ingredient to a monograph – through a TEA or after FDA proposes a change in response to a citizen petition – essentially is a stalled process. FDA is considering potential changes to reinvigorate the process and make it more likely ingredients can be added to the monographs ([A#05140915003]).

“We've had frustration over the years that if some ingredients had been submitted as NDAs they'd probably be approved,” Jenkins said at the meeting.

Werner says he expects sunscreen marketers that submitted TEAs will meet one-on-one with FDA to address data gaps in their applications. “They will work with FDA on those applications; go through the nuts and bolts and specifics of that.”

He said members of Congress who supported passage of SIA are likely “surprised” by the TEA rejections. “I think there will be a lot of inquiries from Congress about this,” he said.

Available Data Leaves Gaps

L'Oreal's ecamsule TEA submitted in 2007 asked FDA to include the ingredient in concentrations up to 10% as an active ingredient in the OTC sunscreen monograph. The following year, the agency said ecamsule in those concentrations was eligible to be considered for inclusion in the monograph and but requested data to support a GRASE determination.

After reviewing information L'Oreal provided on human irritation, sensitization and photosafety studies, FDA concluded the data “are not sufficient to assess the dermal safety of ecamsule in concentrations up to 10 percent and specifically its potential to cause irritation, sensitization, photo irritation, or photoallergenicity.”

“Submission of data from human irritation, sensitization and photosafety studies that meet FDA standards is recommended to demonstrate that an OTC sunscreen product containing up to 10 percent ecamsule is not an irritation, sensitizer, photosensitizer or photo irritant,” according to the proposed order.

The human dermal pharmacokinetic – bioavailability – studies from L’Oreal provided no “useful” information about systemic exposure, according to FDA, which requests the data to assess potential for and the extent of systematic absorption.

FDA also requests from L’Oreal a summary of all available reported adverse events associated with ecamsule, as well as all side effects.

Merck's 2002 TEA proposed enzacamene at concentrations up to 4% for use in sunscreen products. FDA said in 2003 the substance was eligible for inclusion in the monograph at those concentrations and asked for safety and effectiveness data, which Merck submitted in 2003.

FDA concluded that although the human studies Merck submitted suggest enzacamene “may not be a primary irritant, sensitizer, photosensitizer or photo irritant,” each study “has limitations, such as inadequate sample size, lack of blinding, and lack of positive and negative controls, that prevent us from making definitive conclusions.”

The agency requests the submission of additional data from human irritation, sensitization and photosafety studies “to demonstrate that an OTC sunscreen containing up to 4% enzacamene is not an irritation, sensitizer, photosensitizer, or photo irritant.”

Further, FDA said “the data available are incomplete for the assessment of human bioavailability (absorption) of enzacamene. Accordingly, we request data from human pharmacokinetic studies to assess potential for and extent of systemic absorption.” Studies on thyroid safety should also be conducted, according to the agency.

FDA Denies Remaining Sunscreen TEAs, Offers Primer On GRASE, Resources

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