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Toxicity Testing For Topical Drugs, Sunscreens Included

An upcoming FDA workshop on skin safety testing for topical drugs is focused across product categories, but sunscreen sector stakeholders hope the discussions will shed light particularly on the agency's standards for human data on potential skin risks. That threshold, they say, is blocking the introduction of additional ingredients.

FDA does not mention specifically sunscreen or any other Rx or OTC drug type in its recent announcement for its Sept. 10 public workshop, "Human Dermal (Skin) Safety Testing for Topical Drug Products: Regulatory Utility and Evaluation.” The agency's Center for Drug Evaluation and Research, which is conducting the meeting, told thePink Sheetthat neither sunscreens nor other categories are a priority.

"The workshop is not focused on a particular topical drug class or indication," said a center representative. "The context of the workshop arose from the experience of [CDER's] Division of Dermatology and Dental Drug Products; sunscreens are almost exclusively regulated by the Division of Nonprescription Drug Products," the representative noted.

However, while the agency has identified potential skin toxicity risks with topical drugs approved for other indications, the sunscreen category's expansion has been more stifled by the issues of standards for testing, and the resulting impact has attracted more attention from the public health community than any other.

The Public Access to SunScreens Coalition, an advocacy group of manufacturers and public health experts, anticipates that sunscreen ingredients will be a topic at the workshop.

"The workshop provides the opportunity for interested stakeholders to provide input into the agency’s current regime for evaluating topical drug products, including sunscreen ingredients," the coalition said in a statement. "We encourage FDA to use the workshop as an opportunity to be flexible in considering alternative testing regimes for sponsors to meet the agency’s standard for products generally recognized as safe and effective as it seeks to address the known risk of skin cancer. The PASS Coalition looks forward to continuing to serve as a resource for the Agency to ensure that Americans have access to the latest sunscreen technology.”

The OTC drug trade group Consumer Healthcare Products Association points out that numerous categories of topical drugs are available Rx or OTC and could be discussed at the workshop. "We always appreciate the opportunity for dialogue with the agency and other stakeholders. There are many topically-applied drug products, including those marketed as prescription or OTC. FDA didn’t specify a particular category of topical product in the notice so we assume any or all may be discussed at the meeting. We look forward to seeing the agenda and hope that this meeting will provide an opportunity to highlight newer, state-of-the-art, non-animal test methods considered supportive of skin safety," CHPA said in a statement.

The workshop at FDA's White Oak campus headquarters in Silver Spring, Md., will include a morning session with speakers focused on current dermal safety testing – including limitations of the status quo and implications for topical drug product labeling – and an afternoon panel discussion on possible alternative strategies. A 30-minute open public hearing also is scheduled in the afternoon.

Irritancy, Sensitization, Phototoxicity Among Endpoints

With the workshop, CDER intends to offer up-to-date insight into its expectations for skin toxicity data in the context of topical drug reviews. The notice specifies that irritancy, sensitization, phototoxicity and photoallergenicity are endpoints of interest.

CDER says safety data in those areas have been deficient in submissions from companies looking to add sunscreen active ingredients to the agency's corresponding OTC drug monograph. ( (Also see "Sunscreen Group Remains Cloudy About FDA's Ingredient Evaluations" - Rose Sheet, 10 Nov, 2016.))

The center has emphasized that the Sunscreen Innovation Act (SIA) passed in 2014 established mandatory timelines for its review of OTC sunscreen ingredients under pre-existing time and extent application (TEA) terms, but did not change the generally recognized as safe and effective (GRASE) standard to which they’re held.

So while the SIA compelled FDA to clear its OTC sunscreen review backlog, the agency returned all eight pending TEAs to the sponsors with tentative “insufficient data” decisions. The agency has pointed out it did not reject the applications but advised the sponsors they needed additional information on their ingredients' safety before CDER would evaluate whether to add any to the OTC monograph.

CHPA says said CDER's letters to the eight TEA sponsors provided an overview of the type and extent of safety data the center believe is required. That's not going to change in the workshop.

"As noted in the Federal Register, this meeting will be about discussing current approaches and their limitations as well as alternative approaches. Given that this is a public workshop, FDA won’t be setting policy in this meeting," the trade group advised.

Congress Takes Notice

Still, returning the applications left US consumers with an unchanged selection of UV filters and products sponsors with weighty questions as to how they can clear FDA’s GRASE bar and whether their investment is worth the return.

Guidance from FDA on sunscreen data requirements, finalized in November 2016, failed to reassure stakeholders. Sunscreen ingredient firms continue to argue the agency’s GRASE target needs recalibration and its safety assessment framework needs updates to allow for greater flexibility consistent with modern approaches.  ( (Also see "Sunscreen Industry Asks FDA For Flexibility Despite Guidances' Rigidity" - Rose Sheet, 22 Nov, 2016.))

Congress also has gotten involved, dismayed by the enduring lack of next-generation sunscreen actives at a time of epidemic skin cancer rates.

In reports published with legislation on FDA's fiscal year 2019 budget that state their priorities and concerns for its work, House and Senate appropriators urged the agency to work with sunscreen firms to facilitate adding ingredients to the monograph. The Senate Appropriations Committee directed FDA to meet with sunscreen ingredient sponsors to discuss development of a testing regimen in line with current scientific standards “that appropriately balances the benefit of additional skin cancer prevention tools versus the risk of skin cancer." (Also see "Appropriators Agree On Boosting FDA's Supplement Sector Work, Not On Funding" - Rose Sheet, 6 Aug, 2018.)

Additionally, with legislation advancing to reform FDA's OTC drug monograph program as a whole and impose deadlines on agency decisions across the system, the agency may be seeking input on contentious safety issues that have arisen under the SIA or preparing industry for other challenges of the same order. ( (Also see "Exclusivity Period Allowed By OTC Monograph Reform Likely Up To Conference Committee" - Rose Sheet, 19 Jul, 2018.))

Registration for the workshop, including to present during the public hearing, is open until Sept. 4. Comments are due by Oct. 10, docket FDA-2018-N-2582.

Other topical products that have prompted FDA's concerns include silver nanoparticles for their potential migration and toxicity to vaginal tissue when used in feminine hygiene items. The agency said in its fiscal year 2019 budget justification released in April that its NanoCore research facilities in collaboration with the agency’s Office of Women’s Health are evaluating the potential risk. (Also see "Feminine Cleanser Marketing Never Without Challenges; Now The Category Has FDA’s Attention" - Rose Sheet, 18 Apr, 2018.)

Additionally, potential skin toxicity from atopic dermatitis treatments should be considered before enrolling pediatric patients in clinical trials for treating the condition, FDA says. In a draft guidance published in April, it suggested firms consider conducting a juvenile animal toxicity study that incorporates appropriate endpoints before enrolling pediatric AD patients in clinical trials. (Also see "Pediatric Studies Of Systemic Atopic Dermatitis Drugs Should Start Earlier, US FDA Says" - Pink Sheet, 12 Apr, 2018.)

In 2016, FDA and an advisory committee stated concerns about risks other than skin toxicity for the first acne drug made available OTC following its use as an Rx ingredient,Galderma Laboratories Inc.'s Differin Gel. According to a briefing document prepared for an advisory committee considering Galderma Labs' 's proposal to make adapalene gel 0.1% acne treatment available OTC, the agency said it expected a "substantial" number of pregnant women would not accurately self-select the product; the Nonprescription Drugs Advisory Committee unanimously recommended approval of the proposal, but many members also stated reservations about whether the product should be labeled with a warning that women who are pregnant should consult a health care professional before using the drug. (Also see "Galderma Pioneers NDA Path Into OTC Acne Treatment Market" - Rose Sheet, 11 Jul, 2016.)


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