FDA Seeks Comment On Proposed Orders Under Sunscreen Innovation Act

Under the Sunscreen Innovation Act enacted in late 2014, FDA’s tentative determinations on time and extent applications for sunscreen ingredients are now deemed proposed orders and must be made available for public comment. The agency seeks input on six insufficient-data letters issued to sunscreen TEA sponsors in 2014, including its latest to BASF regarding bemotrizinol, marketed as Tinosorb S.

FDA is taking its first steps mandated by the Sunscreen Innovation Act, opening for public comment the six insufficient-data letters it issued in 2014 to sponsors of time and extent applications for sunscreen drug ingredients.

In an announcement slated for publication in the Jan. 7 Federal Register, FDA notes that its “tentative” determinations and feedback on sunscreen TEAs provided to sponsors in 2014 are now deemed proposed sunscreen orders under the SIA, enacted Nov. 26, 2014.

Interested parties will have 45 days from the notice’s publication to submit electronic or written comments on the proposed orders, and sponsors have a 30-day window to submit written requests for a meeting with FDA.

Firms that received letters in 2014 outlining FDA’s initial position on sunscreen TEAs include 3V Inc., [Symrise AG] and co-sponsor [Ego Pharmaceuticals Pty. Ltd.], L’Oreal USA, Inc., BASF AG and BASF subsidiary Ciba Specialty Chemicals Corp. (see table). The letters were filed in public dockets accessible at Regulations.gov.

In each case, FDA found data to be insufficient to classify the sponsor’s sunscreen ingredient as generally recognized as safe and effective (GRASE) and not misbranded for use in over-the-counter sunscreen drug products.

“Accordingly, additional data will be needed,” FDA notes in the announcement.

The SIA amends the Federal Food, Drug and Cosmetic Act to establish an updated process for FDA’s review of TEAs, which seek the addition of ingredients or conditions to corresponding OTC drug monographs on the strength of safety and efficacy data supporting their GRASE status.

Often such data comes from foreign markets where candidate products have been marketed for a “material time” and “material extent,” defined by FDA as a “sufficient quantity” of product marketed for five continuous years in the same country, according to the agency’s website.

Sunscreen products containing active ingredients that are not listed in the OTC sunscreen drug monograph cannot be marketed in the U.S. without an approved new drug application.

Three BASF Applications Tentatively Denied

In November, BASF received its third insufficient-data determination for a sunscreen ingredient TEA in 2014, this time for bemotrizinol, marketed under the Tinosorb S trade name.

FDA identified a number of safety and efficacy data gaps in submissions from Ciba that predated its acquisition by BASF.

In the areas of human irritation, sensitization and photosafety, for example, the agency determined the firm’s 32 reported clinical studies inadequate in that most assessed formulations containing more than one active ingredient and included bemotrizinol at levels between 1% and 7.5% – below the 10% maximum concentration sought for the ingredient’s listing in the OTC sunscreen drug monograph.

FDA cites two studies in which bemotrizinol was the sole active ingredient tested and showed no phototoxicity or photosensitization. “However, definitive conclusions cannot be made … due to insufficient sample size and incomplete study reports that lack information about enrollment criteria and treatment conditions (e.g., justification for light spectrum used in testing),” the agency says.

BASF/Ciba’s blanket assertion that no adverse effects have been reported for bemotrizinol “after 2 billion applications” was not sufficient for FDA, which seeks a more robustly characterized adverse-event profile.

BASF/Ciba’s TEA for bemotrizinol also lacked human dermal pharmacokinetic studies exploring whether dermal application may result in skin penetration and systemic exposure to the ingredient.

FDA notes that it reviewed one study that used human skin samples to evaluate dermal penetration of topically applied bemotrizinol, but “because this study was not designed to detect or quantify bemotrizinol in the blood or other body fluids, it provides no useful information about systemic exposure,” according to the agency’s letter.

FDA also was dissatisfied with adverse-event information submitted in 2005 and 2006 by Ciba to the effect that no adverse effects have been reported for bemotrizinol “after 2 billion applications.”

The agency acknowledges the challenges involved in meeting its expectations for a robustly characterized adverse-event profile. “We recognize that adverse-event data from foreign marketing experience may reflect patterns of use and regulatory reporting requirements that differ from those in the United States; we nonetheless consider such information to be strongly relevant both to our overall GRASE assessment of bemotrizinol for use in sunscreens and to our consideration of potential product labeling.”

FDA advises the firm to explain how adverse events are identified and collected in countries where bemotrizinol is marketed and to provide a written explanation for why information may not be available.

Finally, the agency requests data from animal testing to elucidate the potential long-term dermal and systemic effects of bemotrizinol exposure – specifically, targeted research to determine the ingredient’s potential carcinogenicity, developmental and reproductive toxicity, and toxicokinetic risks.

With regard to efficacy, FDA holds that 19 study reports submitted by BASF’s Ciba unit fell short of regulatory requirements because they evaluated the effectiveness of finished (combination) sunscreen products without clearly defining bemotrizinol’s contribution.

A study taken from published literature did support the effectiveness of bemotrizinol in isolation at 2%, 3% and 5% concentrations. However, FDA asks for “two adequate and well-controlled SPF studies conducted according to established standards to demonstrate that the lowest selected concentration provides an SPF of 2 or more,” as well as a study demonstrating the ingredient’s efficacy at the maximum 10% concentration.

FDA highlighted similar shortcomings in BASF’s TEA for octyl triazone, marketed as Uvinul T 150, in a letter issued to the firm in June 2014 (Also see "FDA Faults BASF Sunscreen Ingredient Data In Latest TEA Rejection" - HBW Insight, 24 Jun, 2014.).

A September 2014 letter from FDA said data supporting the firm’s TEA for bisoctrizole were insufficient largely due to confusion in submitted studies as to what exactly was being tested – bisoctrizole or the commercial product Tinosorb M, which combines bisoctrizole with other ingredients (Also see "BASF Sunscreen Ingredient TEA Suffers Identity Crisis In FDA Review" - HBW Insight, 8 Sep, 2014.).

Timeframes for public comment and sponsor meeting requests figure among deadlines established by the SIA to expedite FDA’s review of pending and new TEAs, though stakeholders have noted that faster review does not guarantee approvals, and more comprehensive revisions to the TEA process and monograph system are needed, some industry representatives say (Also see "Sunscreen TEAs Could Illuminate How Deadlines Influence FDA’s Process" - HBW Insight, 22 Dec, 2014.).

FDA’s Proposed Sunscreen Orders Under SIA
Active Ingredient	Sponsor	Date Issued
Bemotrizinol	BASF AG/Ciba Specialty Chemicals Corp.	11/13/2014
Bisoctrizole	BASF AG/Ciba Specialty Chemicals Corp.	9/3/2014
Drometrizole Trisiloxane	L’Oreal USA, Inc.	8/29/2014
Octyl Triazone	BASF AG	6/23/2014
Amiloxate	Symrise, Inc. Ego Pharmaceuticals Pty. Ltd.	2/25/2014
Diethylhexyl Butamido Triazone	3V Inc.	2/21/2014