L’Oreal Falls Short On Safety, Efficacy, Adverse Event Data
This article was originally published in The Tan Sheet
Executive Summary
FDA says it needs additional data from L’Oreal on safety, efficacy and adverse events to determine GRASE for drometrizole trisiloxane.
[L'Oreal USA Inc.] needs to furnish additional safety and efficacy data and adverse event information to support sunscreen ingredient drometrizole trisiloxane as GRASE, FDA says in its response to the firm’s time-and-extent application to add the ingredient to the OTC sunscreen monograph.
An Aug. 29 letter to L’Oreal says FDA’s Center for Drug Evaluation and Research determined that data in the firm’s TEA for drometrizole trisiloxane are insufficient to determine whether the ingredient is generally regarded as safe and effective. The ingredient, marketed under the trade name Mexoryl XL, is used widely in sunscreen products available in other countries.
L’Oreal could respond to the agency with additional information regarding adverse events associated with drometrizole trisiloxane and specific data on the ingredient’s safety and efficacy.
“L’Oreal USA is pleased that FDA is making progress on the review process of active sunscreen ingredients and we are closely reviewing the response to our application,” Kristina Schake, L’Oreal USA’s chief communications officer, said in a statement. “This sunscreen ingredient has been safely used in Europe for more than a decade, and we look forward to continuing to work with FDA so American consumers have the same access to the next generation of sunscreens that is available in other countries.”
15% Concentration Tests Lacking
The information L’Oreal provided to the agency in 2009 and 2010 to support its TEA for drometrizole trisiloxane in concentrations of up to 15% was not enough to meet FDA’s stringent requirements.
The agency takes issue with L’Oreal’s safety testing that did not feature drometrizole trisiloxane as the sole active ingredient at a 15% concentration, the maximum use level sought in the French firm’s bid for FDA approval.
FDA says it assessed 34 clinical safety studies of more than 2,000 subjects’ exposure to drometrizole trisiloxane. While no serious adverse events associated with the studies were reported, the studies used drometrizole trisiloxane in concentrations from 0.5% to 3%.
Moreover, only three of the studies featured drometrizole trisiloxane as the sole active ingredient, which FDA suggests is the study method that will “allow for more direct assessment” of effects. Additionally, the three studies featured sample sizes insufficient for making definitive conclusions, according to the letter from CDER Office of Drug Evaluation Acting Director Sandra Kweder to L’Oreal Regulatory Affairs Director John Tomaszewski.
FDA requests that L’Oreal provide data to demonstrate drometrizole trisiloxane is not a human irritant, sensitizer, photosensitizer or photo-irritant; and human dermal pharmacokinetic, or bioavailability, studies to determine if the ingredient penetrates the skin. L’Oreal did not provide those studies in its application.
Adverse Event Data Gap Persists
FDA also points out a lack of adverse event information L’Oreal provided in its submission. The agency emphasizes including robust adverse event data in TEAs, in spite of differing reporting requirements outside the U.S. for sunscreen and other OTC drug ingredients.
For instance, in Europe Union member countries sunscreen is considered a cosmetic and is not subject to the EU’s more rigorous adverse event reporting for drugs.
L’Oreal’s TEA submission maintains the firm uses a “cosmetovigilence” system to collect and evaluate post-market safety information and it is not aware of any drometrizole trisiloxane products that were withdrawn from markets due to adverse health claims.
However, FDA looks to establish an adverse event profile for drometrizole trisiloxane and requests a summary of all reported adverse events potentially associated with the ingredient; all available documented case reports of serious side effects; any available safety information from studies of the safety; and effectiveness of sunscreen products containing the ingredient in humans and relevant medical literature describing adverse events associated with the ingredient.
FDA also asks L’Oreal for further data regarding animal studies “that characterize the potential long-term dermal and systemic effects of exposure to” the ingredient.
While L’Oreal’s submission included numerous nonclinical animal studies, the agency offers L’Oreal the opportunity to close data gaps with more robust information on some of the studies, as well as additional studies to address carcinogenicity.
On the efficacy side, FDA requests evidence that drometrizole trisiloxane effectively prevents sunburn. The agency asks L’Oreal to provide results of at least “two adequate and well-controlled SPF studies” at concentrations lower than 15% conducted per FDA’s established standards, in addition to an efficacy study of drometrizole trisiloxane at 15%.
L’Oreal still awaits FDA response on its TEA for ecamsule, marketed as Mexoryl SX. The firm’s new drug application for La Roche-Posay Anthelios 40 – which includes ecamsule as an ingredient – received FDA approval in 2008, but adding an ingredient to an OTC monograph requires either a TEA approval or an amendment proposed through a citizen petition or by the agency (Also see "FDA Deems UVA Filter Ecamsule Eligible For Monograph Inclusion, Seeks Data" - Pink Sheet, 15 Sep, 2008.).