FDA’s rejection of the two remaining sunscreen time-and-extent applications, including one for an ingredient available OTC through the new drug application pathway, signals “nothing’s going to get to market” anytime soon through monograph changes, according to an advisor for the Public Access to Sunscreens coalition.

Both L’Oreal USA Inc.’s ecamsule, already used in multiple OTC sunscreens marketed by the firm through a 2006 NDA approval, and Merck & Co. Inc.’s enzacamene are not generally recognized as safe and effective and therefore misbranded when used in OTC sunscreen products due to insufficient data, FDA said in proposed orders published Feb. 25 in the Federal Register ([A#02150302001]).

With those orders, FDA cleared its queue of long-pending TEAs, but with insufficient-data denials across the board, disappointing many stakeholders who saw passage of the Sunscreen Innovation Act in late 2014 as a guarantee that an updated selection of sun-protection ingredients would soon be available to U.S. consumers.

FDA’s announcement came as a blow to the PASS coalition, whose 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,” observed Werner, a partner at law firm Holland & Knight, in an interview.

“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.

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

FDA maintains that while the SIA established deadlines for FDA’s review of sunscreen TEAs, it did not lower the threshold for demonstrating GRASE – the central criterion for adding ingredients to an OTC monograph.

The agency has invited sponsors of the insufficient TEAs to submit additional data, noting that marketing histories for ingredients available for a material time and to a material extent in countries outside the U.S. do not in themselves fulfill all GRASE data requirements, including information on absorption and long-term effects.

FDA Married To NDA Process?

Werner sees the problem as more systemic. According to the attorney, FDA’s denial of the ecamsule TEA underscores its reluctance to work outside of the NDA process.

Ecamsule, touted as a highly effective UVA filter, was approved in an NDA in 2006, Werner pointed out Also see "L’Oréal’s Anthelios SX Will Launch Following FDA Approval Of UVA Filter" - HBW Insight, 31 July, 2006.. The ingredient, bearing trade name Mexoryl SX, subsequently launched to market in a L’Oreal ParisRevitalift moisturizer and Anthelios products from L’Oreal’s La Roche-Posay division, among other offerings with SPF in the firm’s portfolio.

In a bid for broader use of ecamsule, L’Oreal submitted a TEA for the ingredient in 2007, citing marketing experience in 48 countries for more than five years at the time, only to have its application “languish” in the TEA review process for more than seven years and ultimately be rejected, Werner noted.

“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 acknowledged 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#02150209009]).

It’s not hard to see why FDA would be more comfortable with the NDA process. NDA approvals are product-specific, allowing marketing of an ingredient only within the strictly defined parameters of the approved submission.

Monographs, on the other hand, cover multiple ingredients across an intended-use category, enabling any ingredient added to them, through a TEA for example, to be used in various product formats, in combination with any number of other ingredients, by any firm compliant with FDA manufacturing regulations. The flexibility equals greater liability and therefore rigorous scrutiny by FDA.

While the TEA system was met with optimism from industry and other stakeholders when introduced, adding ingredients to established monographs essentially is a stalled process. FDA is considering potential changes to reinvigorate the process and facilitate data collection necessary to meet the GRASE standard ([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 recent 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.”

Available Data Leaves Gaps

L’Oreal’s ecamsule TEA submitted in 2007 sought the ingredient’s addition to the OTC sunscreen drug products monograph in concentrations up to 10%. The following year, the agency said ecamsule in those concentrations was eligible to be considered for inclusion in the monograph, but requested data to support a GRASE determination Also see "FDA Deems UVA Filter Ecamsule Eligible For Monograph, Seeks Data" - HBW Insight, 15 September, 2008..

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% 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% 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 is asking L’Oreal for 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 that year.

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 additional data from human irritation, sensitization and photosafety studies to demonstrate that an OTC sunscreen containing up to 4% enzacamene is not an irritant or sensitizer by itself or in reaction to sunlight.

In addition, FDA had the same problem with Merck’s bioavailability data as it did with L’Oreal’s, calling Merck’s submission “incomplete” in this respect. The agency seeks data from human pharmacokinetic studies to gain visibility into enzacamene’s potential for systemic absorption. Studies on thyroid safety should also be conducted, according to FDA.

Comments on the proposed orders are due by April 13.

PASS Reacts To Sunscreen TEA Denials: Has FDA ‘Moved The Goal Post’?

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