LOREAL USA. February 6, Theresa Michelle, M.D.

Transcription

1 Theresa Michelle, M.D. LOREAL ~OREAL USA PRODUCTS, Inc. - Clark, NJ ) Chemical structure: 1) Product name: Drometrizole trisiloxane The following information is being provided for the purposes of this request. The purpose of this meeting is to discuss the feedback letter issued to L'Oreal USA on August 29, 2014 relative to our safety and efficacy submission on drometrizole trisiloxane as authorized under the Time and Extent Application procedures in 21 CFR Pursuant to the notice published in the Federal Register dated January 7, 2015 (80 FR ), L'Oreal USA, hereby submits a request for meeting. Dear Dr. Michelle, RE: SPONSOR MEETING REQUEST Drometrizole trisiloxane Docket No. FDA-2003-N-0196 Director, Division of Nonprescription Drug Products Center for Drug Evaluation and Research Food and Drug Administration New Hampshire Avenue Bldg. 22, Rm Silver Spring, MD February 6, 2015 USA

2 OTC sunscreen active ingredient 4) Brief statement of purpose and objective Discussion of the data gaps as detailed in the agency's August 29, 2014 correspondence and presentation of the L'Oreal USA position. Issues to be discussed include: 1. DATA ITEM FDAREQUEST > > ',. <. I WHAT.\1\/AS SUBMITTED Carcinogenicity Studies Conduct systemic (oral) 104 week dermal study carcinogenicity study 52 week photocarcinogenicity Human Dermal PK Conduct human dermal PK No human dermal PK was studies include collection of submitted safety data from regularly scheduled physical exams. Studies should continue until steady-state is reached. Measured parameters should include Cmax, Tmax, AUC, halflife, clearance and volume of distribution. Conduct maximal use trial (MuST) 15% Maximum Submission does not support The majority of human safety Concentration of Mexoryl XL this maximum and SPF testing data were based on formulations at 3% or lower. Human Safety Data Conduct safety studies on Mex 34 clinical safety studies, over XL as sole active ingredient individual subjects, Studies should be in accordance included only combinations. 3 with FDA guidance. studies were done on 15% Mex XL alone. For the three 15% MEX XL alone Phototox N# = 12 studies, protocol exclusion Photoallergy N# =30 criteria not reported, and N# 's HRIPT N# =55 were insufficient. Toxicokinetic Studies Obtain toxicokinetic data from Single dose PK in rats and rabbit. repeat dose (dermal and oral) Multiple dose PK study in exposure rabbits via oral route. 13 week PK in the rat at a dose of 1g/kg/day orally. Effectiveness Data 2 SPF studies (per OTC SPF data from formulations with monograph) on MEX XL as sole multiple active ingredients. active ingredient at a concentration lower that 15%. Including a vehicle control arm 3) Proposed indication:

3 15% Maximum Concentration of Mexoryl XL: L'Oreal agrees to lower the maximum concentration to 3%, based on the totality of the data submitted in the filing. Human Dermal PK: L'Oreal feels that appropriate animal PK data have been submitted that provides useful information for extrapolation to humans. Carcinogenicity Studies: The safety data available for drometrizole trisiloxane include two long term dermal carcinogenicity studies, one of which was a photocarcinogenicity study, which were negative and contain no signals pointing a carcinogenic effect related to the test article. Additionally, the animal PK data available for drometrizole show that there is a very low rate of absorption from oral administration. There were also data submitted from a single dose absorption study in the mouse via the dermal route using a 15% topical solution that shows a plasma concentration of 1892 ng/ ml. Based on this PK and absorption information it is reasonable to expect that there was systemic exposure to drometrizole trisiloxane during the 104 week study, albeit at a low level. The safety profile for drometrizole trisiloxane, based on the totality of the evidence, demonstrates a margin of safety for all toxic effects, including carcinogenesis, well within the acceptable limits as established for over-the-counter drugs marketed in the U.S. 6) Proposed questions and L'Oreal's position on the following: Discussion of all points listed above and the presentation of the L'Oreal USA position and proposal on each. 5) Proposed agenda: Establish AE Profile Nonclinical Studies Genotoxicity Studies DART Studies Submit a written explanation for lack of data from countries where such data was not available. Update literature search for AE's Submit full reports of the 104 week dermal care study in mice and the 13 week dermal study in mice None None Cosmetovigilance data were submitted from the global system from 2003 thru AEs for adults and 1519 for children. 8 case reports for SAEs Full text portions of the Final Study Reports were submitted per concurrence with FDA 7 in vitro studies submitted 1 micronucleus assay in mice via the oral route 6 studies in two species (rat/rabbit) all via oral route Human Safety Data to FDA 'REQlJEsr Submit any additional available post-marketing information ".\NHAT WAS SIJIJI\II.. IJTED

4 Additionally, there are three studies on formulations that contained drometrizole trisiloxane as the sole active sunscreen ingredient. FDA comments that for the three studies containing drometrizole trisiloxane, the patient numbers were not sufficient to support the findings that the ingredient was not Effectiveness Dat a: L'Oreal agrees to conduct two additional SPF studies (following the protocol published by FDA in 2011) at a concentration of drometrizole trisiloxane below the revised maximum Toxicokinetic Studies: In vitro human percutaneous absorption studies indicated that less than 0.5% of the applied drometrizole trisiloxane was found in the dermis+ receptor fluid. In vivo percutaneous absorption studies of 14 C radiolabeled drometrizole trisiloxane after a single topical application in mice and rats confirmed the low percutaneous penetration rate of the substance with mean plasma Cmax of ~g-equivalent/g in mice or 2.56 ng-equivalent/g in rats. It was concluded that in both species, systemic exposure due to percutaneous absorption was minimal. While a mean value of approximately 1.9 ~g-eq/ml plasma was measured at sacrifice in mice receiving daily topical applications of a formulation containing 15% drometrizole trisiloxane for 13-weeks, oral absorption due to grooming and licking could not be excluded. After a single oral administration of drometrizole trisiloxane in rats, mean plasma Cmax reached 2.08 ~geq/g. After repeated oral administration for 4 or 13 weeks in the 90-day toxicity study, the plasma concentration reached approximately 1 ~g/ml plasma suggesting that drometrizole trisiloxane is systemically absorbed by the oral route but with a limited bioavailability. Results of in vitro metabolism by rat hepatocytes and by hepatic rat and human microsomes indicated that about 80% of the test substance remained unchanged. There was no difference in metabolisation between both species. These results indicate that the rat is a suitable predictor for human toxicity. No ADME study was performed, as the rates of distribution/elimination were expected too low for obtaining significant results. Given that dermal penetration rates in rats tend to be 2 to 5 fold higher than respective values in humans, the amount of human absorption may be estimated to be <0.1% of a topically applied dose. Such absorption rates may be considered to be negligible for non-toxic compounds. Given t he low dermal penetration rates, the low oral absorption rate, and the similarity in rodent and human metabolism, it is felt that no additional toxicokinetic data are necessary. an irritant or sensitizer. When taken in the aggregate, the number of subjects exposed to drometrizole trisiloxane from all submitted studies far exceeds the number of subjects FDA requires for each of the types of studies. The weight of the evidence from these studies along with the extensive post-marketing safety information available, indicates that drometrizole trisiloxane is safe for application to human skin as a sunscreen. L'Oreal appreciates the Agency's desire to assure that other ingredients may in some way potentiate or mask effects of this ingredient; however, if this were the case a signal would have surfaced given the length of marketing history and extent of the safety study database. Human Safety Data: Numerous human safety data on various formulations were submitted. All the formulations included drometrizole trisiloxane along with numerous other sunscreen active ingredients.

5 drometrizole trisiloxane. These studies will be conducted in a qualified US laboratory. Human Safety Data to Establish an AE Profile: L'Oreal agrees to update the AE database in the format Face-to- Face 10) Format of Meeting: Per the Sunscreen Innovation Act, L'Oreal suggests that the meeting be convened within 45 days of the date of this letter, preferably the week of March 16, 2015, excluding Friday March 20. We would prefer a meeting time in the early afternoon. 9) Suggested time and dates: L'Oreal requests that a senior level FDA toxicologist /pharmacologist be present at the meeting 8) List of FDA Staff: L' Oreal attendees will be: Steve Martin, VP Safety, Regulatory and Claims {SRC} Americas John Tomaszewski, Director Regulatory Affairs Non-Cosmetic Thomas Re, Senior Principal Scientist US Safety Evaluation 7) List of attendees: DART Studies: Confirmation that sufficient data have been submitted. Genotoxicity Studies: Confirmation that sufficient data have been submitted. Nonclinical Studies: The submission of the study reports within this TEA was made in accordance and agreement with the Agency's request. Given the scope of what this would entail, in terms of volume of information we would like to discuss other alternatives with the agency, such as limiting the amount of information to the essential elements and/or agreement to submit specific sections. submitted to the original TEA, current up to the date of this request. We do, however, ask for clarification of the Agency's request to submit a written explanation for lack of data from countries where such data were not available. concentration of 3%. We will utilize an active formulation similar to the placebo formulation specified in the FDA monograph methodology, except for the inclusion of the specified concentration of

6 Thank you for consideration of this matter. Respectfully, Jo n omaszeswki Director Regulatory Affa' L'Oreal USA Products, Inc. 133 Terminal Avenue Clark, NJ 07066